Adult North Star Network (ANSN): Consensus Guideline For The Standard Of Care Of Adults With Duchenne Muscular Dystrophy.

There are growing numbers of adults with Duchenne Muscular Dystrophy living well into their fourth decade. These patients have complex medical needs that to date have not been addressed in the International standards of care. We sought to create a consensus based standard of care through a series of multi-disciplinary workshops with specialists from a wide range of clinical areas: Neurology, Cardiology, Respiratory Medicine, Gastroenterology, Endocrinology, Palliative Care Medicine, Rehabilitation, Renal, Anaesthetics and Clinical Psychology. Detailed reports of evidence reviewed and the consensus building process were produced following each workshop and condensed into this final document which was approved by all members of the Adult North Star Network including service users. The aim of this document is to provide a framework to improve clinical services and multi-disciplinary care for adults living with Duchenne Muscular Dystrophy.

Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging.

BACKGROUND AND PURPOSE: The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. METHODS: Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1-weighted and short-tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. RESULTS: The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro-caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. CONCLUSION: This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD-related disease spectrum.

Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

Why are some patients with Duchenne muscular dystrophy dying young: An analysis of causes of death in North East England.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. METHOD: A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). RESULTS: Detailed information was available on 21 patients. Mean age of death in group 1 (17 patients) was 23.9 (14.4-39.5) years, in group 2 (4 patients) 14 (12.7-14.9) years. Causes of death in group 2 were acute pneumonia, cardiac arrest, acute respiratory distress and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. CONCLUSIONS: The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death.

Myopathy secondary to intravascular large B-cell lymphoma.

We report a case of a 78-year-old woman presenting with progressive proximal muscle weakness mainly to lower limbs and myopathic EMG associated with intravascular large B-cell lymphoma. Muscle biopsy showed myopathic changes, intravascular large B-cell lymphoma but no inflammation or fibre necrosis; the patient's serum cross-reacted with an unidentified nuclear antigen of approximately 45 kDa present in muscle and lymphoma cells. Our case illustrates a myopathy associated with intravascular large B-cell lymphoma probably mediated by antibodies cross-reacting with a nuclear protein expressed by neoplastic cells and normal muscle. The nature of this nuclear antigen remains unidentified.

Case report of adult-onset Allgrove syndrome.

Allgrove syndrome is a rare autosomal recessive disorder characterised by childhood onset, alacrima, oesophageal achalasia, adrenocortical insufficiency, neurological and occasionally autonomic involvement. Although the disease has been associated with mutations in the ALADIN gene on chromosome 12q13, it is genetically heterogeneous. The case we report is interesting because of its onset in adulthood, long duration of disease and prominent neurological dysfunctions. After the onset of neurological abnormalities the diagnosis went unrecognised for years until the patient presented for evaluation of dysphagia. The presence of achalasia with dysphagia, adrenal insufficiency, reduced tear production, optic atrophy and peripheral motor-sensory neuropathy with axonal loss led us to clinically diagnose Allgrove syndrome even though a genetic study showed no mutations in the ALADIN gene exons. The case we report shares many clinical features with Allgrove syndrome and, even with the limitations of a single case, underlines the variability in this syndrome and the need for appropriate investigations along with a multidisciplinary approach.

Topiramate and cortical excitability in humans: a study with repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) delivered at 5 Hz frequency and suprathreshold intensity progressively increases the size of muscle evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. The aim of this study was to evaluate the effects of topiramate (TPM) at different doses on cortical excitability variables tested with rTMS. We tested the facilitation of the MEP size and CSP duration evoked by focal rTMS in eight patients before and after treatment with TPM at different doses for chronic neuropathic pain. In each patient, rTMS (5 Hz frequency-120% resting motor threshold) was applied at baseline and during the TPM induction phase (drug intake schedule: week I 25 mg/day, week II 50 mg/day, week III 75 mg/day, week IV 100 mg/day) and total TPM plasma concentrations were measured. The effects on the MEP size of 5 Hz-rTMS delivered over repeated sessions were tested in eight control subjects. TPM had no effect on the resting motor threshold. Antiepileptic treatment at increasing doses abolished the normal rTMS-induced MEP facilitation. ANOVA showed that this was a dose-related effect. Accordingly, in patients receiving TPM at higher doses (75 and 100 mg) rTMS failed to elicit the MEP facilitation. TPM left the progressive lengthening of the CSP during the rTMS train unchanged. In control subjects, rTMS applied over repeated sessions elicited a constant increase in MEP size. Our results suggest that TPM modulates the excitatory intracortical interneurons probably by altering rTMS-induced synaptic potentiation. These drug-induced effects are related to TPM doses and plasma concentrations. In conclusion, rTMS may be useful for quantifying the effectiveness of antiepileptic drugs and for assessing individual responses to different drugs but acting through similar mechanisms, thus combining functional neurophysiological information and laboratory data.