S. Vohanka

Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes

Laminopathies represent a heterogeneous group of genetic disorders characterised by mutations in the LMNA gene, which encodes two lamins, A and C, by alternative splicing of the primary transcript.1 Lamins belong to the intermediate filament multigene family and form the nuclear lamina, a mesh-like structure adjacent to the nucleoplasmic side of the inner nuclear membrane.2 They interact with emerin, the proteins encoded by the gene for the X-linked (X EDMD) form of EDMD, with several nuclear envelope proteins and with chromatin. Despite their widespread distribution and their role in nuclear architecture, alterations of lamin A/C are responsible for a number of very specific but quite heterogeneous disorders. The first laminopathy was the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD), a genetic disorder characterised by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects.3 The finding that emerin, an inner nuclear envelope protein, and LMNA were both involved in EDMD suggested that the lamins may represent specific and relevant factors in cardiac and skeletal muscle and that integrity of the nuclear membrane and associated structures is specifically required for muscle function. However, later on it was found that besides autosomal dominant Emery–Dreifuss muscular dystrophy (AD-EDMD), mutations in LMNA are responsible for six other disorders: limb girdle muscular dystrophy 1B, (LGMD1B),4,5 dilated cardiomyopathy with conduction system disease, (DCM-CD),6 Dunningan-type familial partial lipodystrophy,7–9 one recessive axonal form of Charcot-Marie-Tooth neuropathy,10 mandibuloacral dysplasia,11 and Hutchinson Gilford progeria.12,13 Despite the very different phenotypic consequences of mutations in LMNA , and the quite large number of mutations identified, no genotype/phenotype correlation has been demonstrated, pointing to the role of factors other than lamins A and C in determining the different tissue specific phenotypes. …

Poststroke delirium incidence and outcomes: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).

Objective: To describe the epidemiology and time spectrum of delirium using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and to validate a tool for delirium assessment in patients in the acute poststroke period. Design: A prospective observational cohort study. Setting: The stroke unit of a university hospital. Patients: A consecutive series of 129 patients with stroke (with infarction or intracerebral hemorrhage, 57 women and 72 men; mean age, 72.5 yrs; age range, 35–93 yrs) admitted to the stroke unit of a university hospital were evaluated for delirium incidence. Interventions: None. Measurements and Main Results: Criterion validity and overall accuracy of the Czech version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were determined using serial daily delirium assessments with CAM-ICU by a junior physician compared with delirium diagnosis by delirium experts using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria that began the first day after stroke onset and continued for at least 7 days. Cox regression models using time-dependent covariate analysis adjusting for age, gender, prestroke dementia, National Institutes of Stroke Health Care at admission, first-day Sequential Organ Failure Assessment, and asphasia were used to understand the relationships between delirium and clinical outcomes. An episode of delirium based on reference Diagnostic and Statistical Manual assessment was detected in 55 patients with stroke (42.6%). In 37 of these (67.3%), delirium began within the first day and in all of them within 5 days of stroke onset. A total of 1003 paired CAM-ICU/Diagnostic and Statistical Manual of Mental Disorders daily assessments were completed. Compared with the reference standard for diagnosing delirium, the CAM-ICU demonstrated a sensitivity of 76% (95% confidence interval [CI] 55% to 91%), a specificity of 98% (95% CI 93% to 100%), an overall accuracy of 94% (95% CI 88% to 97%), and high interrater reliability (&kgr; = 0.94; 95% CI 0.83–1.0). The likelihood ratio of the CAM-ICU in the diagnosis of delirium was 47 (95% CI 27–83). Delirium was an independent predictor of increased length of hospital stay (hazard ratio 1.63; 95% CI 1.11–2.38; p = .013). Conclusions: Poststroke delirium may frequently be detected provided that the testing algorithm is appropriate to the time profile of poststroke delirium. Early (first day after stroke onset) and serial screening for delirium is recommended. CAM-ICU is a valid instrument for the diagnosis of delirium and should be considered an aid in delirium screening and assessment in future epidemiologic and interventional studies in patients with stroke.

Differential diagnostics in patients with mild lumbar spinal stenosis: the contributions and limits of various tests

Abstract. Lumbar spinal stenosis (LSS) and diabetic polyneuropathy are common ailments of older age. Many people suffer from both at the same time. In such patients it may sometimes be difficult to separate signs and symptoms that could be attributed to either disease. This study evaluates the contributions and limits of various tests, especially the exercise treadmill test (ETT) and electrophysiological examination, in the diagnostics of patients with mild LSS. Twenty-nine patients with mild LSS documented by computed tomography (CT) participated in this study. Sixteen of the patients had neurogenic claudication (LSS NC+), and 13 patients did not (LSS NC–). Patients with LSS were compared with a group of 24 patients with diabetic polyneuropathy and 25 healthy volunteers. The distance covered, the time spent walking and the reasons for preliminary termination of the ETT were evaluated in all groups. Initial electrophysiological examination included electromyography (EMG) from the upper and lower extremities and motor evoked potentials (MEPs) to the lower extremities. LSS NC+ patients covered a significantly shorter distance and the time spent walking was significantly shorter than in LSS NC– patients and in the two control groups. The main reason for preliminary termination of the ETT was the development of NC in 67% of the LSS NC+ patients. In contrast, no LSS NC– patient and none from the control groups revealed NC, but 31% of LSS NC– patients were not able to finish the ETT for other reasons (e.g. dyspnoea). Electrophysiological parameters evaluated from the upper extremities distinguished diabetic patients from LSS patients. The latencies of the tibial F-wave, soleus H-reflex and spinal MEP response reliably distinguished healthy volunteers from diabetic patients and LSS patients, and particularly LSS patients from diabetic patients. The chronodispersion of the tibial F-wave distinguished LSS NC+ patients from the other groups. The results of the study show that electrophysiological examination contributes to the differential diagnostics between mild lumbar spinal stenosis and diabetic polyneuropathy. The contribution of electrophysiological methods in verification of NC in LSS patients is limited (chronodispersion of the tibial F-wave only). The ETT is useful in confirmation of NC and walking capacity verification, but restriction of walking capacity should be carefully analysed.

A mutation in the X-linked Emery–Dreifuss muscular dystrophy gene in a patient affected with conduction cardiomyopathy

A screening for mutation in the X-linked Emery-Dreifuss muscular dystrophy (X-EMD) gene was performed among patients affected with severe heart rhythm defects and/or dilated cardiomyopathy. Patients were selected from the database of the Department of Cardiology of the University Hospital Brno. One patient presented a mutation in the X-EMD gene and no emerin in his skeletal muscle. The patient had a severe cardiac disease but a very mild muscle disorder that had not been diagnosed until the mutations was found. This case shows that mutations in X-EMD gene, as it was shown for autosomal-dominant EMD, can cause a predominant cardiac phenotype.

Dynamic electrophysiological examination in patients with lumbar spinal stenosis: Is it useful in clinical practice?

Neurogenic claudication (NC) is typical of lumbar spinal stenosis (LSS). One suspected pathophysiological mechanism underlying NC is intermittent hypoxia of cauda equina fibres resulting from venous pooling, which may lead to ischaemic nerve conduction failure and to transient clinical and electrophysiological changes after exercise. The aim of this study was to evaluate the appearance of significant transient electrophysiological abnormalities after walking exercise in patients with LSS and to establish the contribution of dynamic electrophysiological examination in the differential diagnostics of patients with LSS. The study participants were 36 consecutive patients with LSS demonstrated by computed tomography (CT). The control groups included, respectively, 28 patients with diabetes mellitus and clinically manifested polyneuropathy, and 32 healthy volunteers. The LSS patients were divided into four subgroups based on the clinical severity of the disease (with respect to the presence or absence of NC in the history and pareses on neurological examination). Soleus H-reflex, tibial F-wave and motor evoked potentials (MEPs) to abductor hallucis muscle were examined in all groups, before and after quantified walking on a treadmill. The electrophysiological parameters measured after an exercise treadmill test (ETT) in LSS patients and in both control groups were compared with the same parameters obtained before ETT. The study shows that the electrophysiological parameters reveal minimal but statistically significant changes after walk loading in patients with LSS (a prolongation of the minimal latency of the tibial F-wave and of the latency of the soleus H-reflex). The changes in these parameters were demonstrated not only in patients with NC but also in patients without NC. More pronounced changes were found in LSS patients exhibiting chronic lower extremity pareses. Conclusions: From among a large battery of electrophysiological tests, only the minimal latency of the tibial F-wave and the latency of the soleus H-reflex exhibit changes after walk loading in patients with LSS. These are minimal but statistically significant. Dynamic electrophysiological examination can illustrate the pathophysiology of NC in LSS, but from a practical point of view its contribution to the differential diagnostics of LSS or diabetic polyneuropathy is limited by an absence of established cut-off values.

Towards a predictive model for post-stroke delirium

Primary objective: To assess predisposing and precipitating risk factors and create a predictive model for post-stroke delirium. Research design: A prospective observational study in a cohort of consecutive patients with ischemic stroke or intracerebral haematoma admitted within 24 hours of stroke onset. Methods: Patients were assessed daily for delirium during the first week by means of DSM-IV criteria and risk factors were recorded. Results: One hundred patients completed a 7-day evaluation (47 women and 53 men, median age 77 years). An episode of delirium was detected in 43 patients (43%). Using multivariate logistic regression, a predictive statistical model was developed that utilized independent risk factors: age (OR = 1.08; 95% CI = 1.02–1.15); intracerebral haemorrhage (OR = 6.11; 95% CI = 1.62–22.98), lesion volume > 40 ccm (OR = 3.99; 95% CI = 1.29–12.39) and either elevated gamma-glytamyl transferase (OR = 4.88; 95% CI = 1.45–16.35) and elevated serum bilirubin (OR = 3.70; 95% CI = 1.32–10.38) or maximum sequential organ failure assessment score >2 (OR = 3.33; 95% CI = 1.06–10.45) with acceptable sensitivity and specificity (69.0% and 80.7%). In ischemic strokes, total anterior circulation infarctions were more frequently associated with delirium (73.3% developed delirium) compared with the remainder of the groups combined (p = 0.004; OR = 6.66; 95% CI = 1.85–24.01). Conclusion: Higher age, metabolic disturbances, intracerebral haemorrhage and larger ischemic hemispheric strokes increase the risk of post-stroke delirium.

The screening for X-linked Emery-Dreifuss muscular dystrophy amongst young patients with idiopathic heart conduction system disease treated by a pacemaker implant.

The X‐linked Emery–Dreifuss muscular dystrophy (X‐EDMD) is a hereditary muscle disorder associated with cardiac involvement. Sinus node dysfunction and atrioventricular conduction defects, typical of X‐EDMD, occur in both males and females and may result in sudden cardiac death unless treated by permanent pacing. The objective of the study was to determine the frequency and relevance of X‐EDMD in heart conduction system disease in young individuals treated with a pacemaker implant. The medical history of 3450 paced individuals in the region of South Moravia, Czech republic, was reviewed. Thirty‐five patients, 20 males and 15 females, with idiopathic heart conduction disease of onset before age 40 were identified and screened for X‐EDMD. Within these 35 individuals, only one male was found to carry a mutation in X‐EDMD gene. We conclude that the clinical relevance of X‐EDMD in heart conduction system disease is very low. It should, however, be included into the diagnostic work‐up of young male individuals with idiopathic cardiac conduction disturbances.

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease

BackgroundMyotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania).ResultsThe registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact.ConclusionsThe community should consider how to maximise this collective resource in future therapeutic programmes.

G.P.250

The patient registries belong to the core activities which can help us in planning of the effective health care, assessing standards of diagnosis and care, and answer the questions concerning on epidemiologic data. Besides of the local hospital-based databases and registries we can find in Czech Republic four national registries of hereditary neuromuscular disorders associated under unique name: ReaDy (registry of muscular dystrophy). Four registries are currently running: Duchenne/Becker muscular dystrophy (DMD/BMD), spinal muscular atrophy (SMA), myotonic disorders (MD), and facioscapulohumeral muscular dystrophy (FSHD). Each registry is independent and has its own curator. The registries are under the supervision of Czech neuromuscular society. The technology, the data collection, the storage, the backup, and analyses are provided by the Institute of Biostatistics and Analyses, Masaryk University, Brno, CR. On-line data collection is based on a TRIALDB system developed on Yale University, Connecticut, USA, which is widely used for this purpose. For each patient is generated a unique ID; all data transfer is encrypted and the system is designed to prevent their unauthorized use during data transfer. Laws and regulations in CR require having an informed consent from all patients whose data are used in the registry. All claims for personal data protection were met. Data are stored on the central server on Masaryk University in Brno in Oracle 9i database. Since 2011 to the March 2014 796 Czech patients were collected: 370 DM, 277 DMD/BMD, 89 FSHD, and 60 SMA. The majority (76%) of all records are from two centers (Prague and Brno). The average annual increase during last three years is 96 patients. The biggest acquisition reveal patients with myotonic disorders (about 45 per year), the smallest growth has the registry FSHD with approx. 11 patients per annum.

G.P.249

Myotonic dystrophy (DM) is a multisystem disorder characterized by skeletal muscle and multiple organ impairment. The aim of the study is to compare our local data from the registry with that known in other countries. The data from the local part of Czech national registry of myotonic dystrophy including focused questionnaires were evaluated. The population consists of 107 patients: 28 DM type 1 mean age 42.6 (range, 23–63), 79 DM type 2 mean age 54.1 (range, 22–76); 67 females and 40 males. One of the most common complaints of patients was muscle pain. Long-term prevalence of muscle pain occurred in 63.6% of patients (71.4% of DM type 1 and 60.8% of DM type 2). Half of the patients (52.4%) suffered from excessive daytime sleepiness in varying degree of intensity. Cognitive dysfunction had 8.6% of our patients, but mostly in DM type 1. Diabetes mellitus or impaired glucose tolerance were found in 21.5% of patients and thyroid dysfunction in 17.4%. Increased sweating indicated 44.8% of patients. Dysphagia was found in 27.8% and 55.8% of patients had fecal incontinence (15.1% was never able to prevent the incontinence of loose stools and 29.1% was not able to prevent the incontinence of solid stool). More than half of the patients (51.2%) reported stress incontinence (during exercise, coughing or sneezing) and 41.9% have other various forms of the urinary incontinence. Our results are consistent with previously published data. We found surprisingly high frequency of bowel incontinence which was not so far comprehensively studied.