Quantitative whole-body muscle MRI in idiopathic inflammatory myopathies including polymyositis with mitochondrial pathology: indications for a disease spectrum.

OBJECTIVE: Inflammatory myopathies (IIM) include dermatomyositis (DM), sporadic inclusion body myositis (sIBM), immune-mediated necrotizing myopathy (IMNM), and overlap myositis (OLM)/antisynthetase syndrome (ASyS). There is also a rare variant termed polymyositis with mitochondrial pathology (PM-Mito), which is considered a sIBM precursor. There is no information regarding muscle MRI for this rare entity. The aim of this study was to compare MRI findings in IIM, including PM-Mito. METHODS: This retrospective analysis included 41 patients (7 PM-Mito, 11 sIBM, 11 PM/ASyS/OLM, 12 IMNM) and 20 healthy controls. Pattern of muscle involvement was assessed by semiquantitative evaluation, while Dixon method was used to quantify muscular fat fraction. RESULTS: The sIBM typical pattern affecting the lower extremities was not found in the majority of PM-Mito-patients. Intramuscular edema in sIBM and PM-Mito was limited to the lower extremities, whereas IMNM and PM/ASyS/OLM showed additional edema in the trunk. Quantitative assessment showed increased fat content in sIBM, with an intramuscular proximo-distal gradient. Similar changes were also found in a few PM-Mito- and PM/ASyS/OLM patients. In sIBM and PM-Mito, mean fat fraction of several muscles correlated with clinical involvement. INTERPRETATION: As MRI findings in patients with PM-Mito relevantly differed from sIBM, the attribution of PM-Mito as sIBM precursor should be critically discussed. Some patients in PM/ASyS/OLM and PM-Mito group showed MR-morphologic features predominantly observed in sIBM, indicative of a spectrum from PM/ASyS/OLM toward sIBM. In some IIM subtypes, MRI may serve as a biomarker of disease severity.

Economic evaluation of Motor Neuron Diseases: a nationwide cross-sectional analysis in Germany.

BACKGROUND AND OBJECTIVES: Motor Neuron Diseases (MND) are rare diseases but have a high impact on affected individuals and society. This study aims to perform an economic evaluation of MND in Germany. METHODS: Primary patient-reported data were collected including individual impairment, the use of medical and non-medical resources, and self-rated Health-Related Quality of Life (HRQoL). Annual socio-economic costs per year as well as Quality-Adjusted Life Years (QALYs) were calculated. RESULTS: 404 patients with a diagnosis of Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) or Hereditary Spastic Paraplegia (HSP) were enrolled. Total annual costs per patient were estimated at 83,060€ in ALS, 206,856€ in SMA and 27,074€ in HSP. The main cost drivers were informal care (all MND) and disease-modifying treatments (SMA). Self-reported HRQoL was best in patients with HSP (mean EuroQoL Five Dimension Five Level (EQ-5D-5L) index value 0.67) and lowest in SMA patients (mean EQ-5D-5L index value 0.39). QALYs for patients with ALS were estimated to be 1.89 QALYs, 23.08 for patients with HSP and 14.97 for patients with SMA, respectively. Cost-utilities were estimated as follows: 138,960€/QALY for ALS, 525,033€/QALY for SMA, and 49,573€/QALY for HSP. The main predictors of the high cost of illness and low HRQoL were disease progression and loss of individual autonomy. CONCLUSION: As loss of individual autonomy was the main cost predictor, therapeutic and supportive measures to maintain this autonomy may contribute to reducing high personal burden and also long-term costs, e.g., care dependency and absenteeism from work.

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers' Lives.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (rp = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (rs = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (ß = -1.96 per increase of one point in the ALSFRS-R score, p < 0.001). "Limb-onset" ALS (lALS) was associated with a better QoL than "bulbar-onset" ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (ß = -7.60, p = 0.001), being tracheostomized (ß = -14.80, p = 0.004) and using non-invasive ventilation (ß = -5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (ß = 5.95, p = 0.007), and increasing age (ß = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.

Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

Associations between histogram analysis parameters derived from morphological sequences and histopathological tissue alterations in myositis and other myopathies: a preliminary study.

OBJECTIVES: Magnetic resonance imaging (MRI) is a cornerstone in diagnosis of myopathies. Recently, imaging techniques, such as histogram analysis are used to obtain novel imaging biomarkers. The present study sought to elucidate possible associations between histopathology derived from muscle biopsies and histogram parameters derived from clinical MRI in myositis and other myopathies. METHODS: 20 patients with myopathies were included in this retrospective study. MRI was performed using a 1.5T MRI scanner including T2- and T1- weighted images. The histogram parameters of the MRI sequences were obtained of the biopsied muscle. The histopathology analysis included the scoring systems proposed by Tateyama et al., Fanin et al., Allenbach et al. and immunohistochemical stainings for MHC-I, CD68, CD8 and CD4. RESULTS: Entropy derived from T2-weighted images showed strong positive associations with the inflammation scores (r=0.71, p=0.0005 with Allenbach et al score and r=0.68, p=0.001 with Tateyama score). Furthermore, there were strong associations between entropy derived from T2-weighted images with MHC-I staining (r=0.67, p=0.022), with the amount of CD20 cells (r=0.70, p=0.022), with the amount of CD4 positive cells (r=0.78, p=0.0075) and with the amount of CD8 positive cells (r=0.79, p=0.004). Other parameters showed no associations with the investigated histopathology features. CONCLUSIONS: Entropy derived from T2-weighted images showed strong associaitions with inflammation scores and with the sole amount of immune cells in myopathies. These results need to be confirmed by clinical studies, whether it is also related to clinical performance or can predict treatment response.

Associations between apparent diffusion coefficient values and histopathological tissue alterations in myopathies.

OBJECTIVES: Diffusion-weighted imaging (DWI) can reflect histopathologic changes in muscle disorders. The present study sought to elucidate possible associations between histopathology derived from muscle biopsies and DWI in myositis and other myopathies. METHODS: Nineteen patients (10 women, 52.6%) with a mean age 51.43 ± 19 years were included in this retrospective study. Apparent diffusion coefficients (ADC) were evaluated with a histogram approach of the biopsied muscle. The histopathology analysis included the scoring systems proposed by Tateyama et al., Fanin et al., Allenbach et al. and immunhistochemical stainings for MHC, CD68, CD8, and CD4. RESULTS: There was a tendency that skewness was lowered with increasing Tateyama score, but it did not reach statistical significance (p = .14). No statistical differences for the other scores were identified. There was a tendency that kurtosis was higher in MHC negative stained patient compared to positive patients, but statistically significance was not reached (p = .07). ADC histogram parameters did not correlate with CD68 and CD8 positive stained cells. There was a trend for skewness to correlate with the amount of CD4-positive cells (r = .57, p = .07). CONCLUSION: The present study could not identify statistical significant associations between DWI and histopathology in muscle diseases based upon a small patient sample. Presumably, the investigated histopathology scores are more specific for certain disease aspects, whereas ADC values reflect the whole cellularity of the investigated muscle, which might cause the negative results.

Associations between magnetic resonance imaging and EMG findings in myopathies.

OBJECTIVES: Magnetic resonance imaging (MRI) is a cornerstone in diagnosis of myopathies. The present study sought to elucidate possible associations between electromyography (EMG) findings and histogram parameters derived from clinical MRI in myositis and other myopathies. MATERIALS AND METHODS: Twenty six patients with myopathies were included in this retrospective study. Clinical MRI was performed with a 1.5T MRI scanner including T2- and T1-weighted images. EMG analysis was performed during clinical diagnostic workup. The histogram parameters of the MRI sequences were obtained of the same muscle, which was investigated with EMG. RESULTS: Several correlations were identified between mean duration of the motor unit potentials (MUP) and histogram parameters derived from T1- and T2-weighted images. The highest for T1-weighted images was mode (r = -.73, P < .0001) and for T2-weighted images was p25 (r = -.57, P = .022). There were significant differences for several histogram parameters between muscles with pathological spontaneous activity and without. So, for T1-weighted images, the best discrimination was achieved with mean (P = .096), and for T2-weighted images for p10 (P = .05). Mean SI values derived from T1-weighted images achieved an AUC of 0.84 with a sensitivity of 0.81 and a specificity of 0.86 to discriminate patients with and without pathological spontaneous activity (PSA). CONCLUSIONS: The present study identified strong associations between histogram analysis derived from morphological MRI sequences and the duration of the MUP derived from EMG in myopathies strengthening the fact that both diagnostic modalities can reflect disease state in a similar fashion. Histogram parameters can predict muscles with PSA.

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.

[Gene-specific treatment approaches in muscle diseases]. / Genspezifische Therapieansätze bei Muskelerkrankungen.

Gene-specific treatment for hereditary muscle diseases has made great progress in recent years. The pathomechanisms of many of these diseases could be decrypted using molecular genetic techniques, paving the way for disease-modifying treatment options. A milestone was undoubtedly the successful translation of the antisense oligonucleotide (ASO) technology into clinical practice, with gene-specific ASOs being approved for the first time in 2016 for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy. This article reviews recent developments in the field of antisense and gene therapies for hereditary muscle diseases.

White matter lesions in treated late onset Pompe disease are not different to matched controls.

INTRODUCTION: Genetic deficiency of α-1,4-glucosidase leads to multi-systemic glycogen storage and causes muscular disorder known as classic infantile Pompe disease (CIOPD) and late onset Pompe disease (LOPD). Treatment with recombinant human alglucosidase alfa is available as enzyme replacement therapy (ERT). Recently progressive white matter lesions (WML) have been observed as a new phenotype in CIOPD patients on treatment with ERT. OBJECTIVE: To investigate the impact of disease and ERT for the development of WML in LOPD. METHODS: WML were analysed in 19 treated LOPD patients and compared with findings of 38 matched controls. RESULTS: Patients median age was 54.4 years (range 19 to 82 years) with median disease duration of 7 years (range 2 to 40 years). Median ERT duration was 63 months (range 9 to 135 months). Grading of WML by Fazekas Score was not different in LOPD patients and controls: Mean of total Fazekas score in LOPD was 2.42 ±â€¯2.40 and in controls 1.60 ±â€¯2.64; p = 0.68. Also volume of WML was similar in patients and controls (mean 5.27 ml ±â€¯5.88 and 7.89 ml ±â€¯11.40 respectively, p = 0.35). Total Fazekas grade correlated directly with the age in LOPD patients (r = 0.60; p = 0.007) and in controls (r = 0.32; p = 0.04). There was a negative correlation of ERT duration and total Fazekas grade (r = -0.41; p = 0.04). CONCLUSION: The study suggests that WML in LOPD mainly result from concomitant cerebrovascular risk factors rather than from the Pompe disease itself.

Decreased outlet angle of the superior cerebellar artery as indicator for dolichoectasia in late onset Pompe disease.

BACKGROUND: Lysosomal α-glucosidase deficiency (Pompe disease) not only leads to glycogen accumulation in skeletal muscle, but also in the cerebral arteries. Dolichoectasia of the basilar artery (BA) has been frequently reported. Therefore progression of BA dolichoectasia in late onset Pompe patients (LOPD) was studied. METHODS: BA length, diameter and volume, and cerebral lesions were analysed by MRI/TOF-MR angiography or CT/CT angiography in 20 LOPD patients and 40 controls matching in age, sex- and cardiovascular risk factors. The height of BA bifurcation was assessed semi-quantitatively using the Smoker's criteria and quantitatively by measuring the outlet angle of the superior cerebellar artery (SUCA). Nine patients were followed over 5 years. RESULTS: The height of the BA bifurcation was abnormal in 12/20 (60%) LOPD patients and in 12/40 (30%) matched controls. The SUCA outlet angle was reduced in LOPD patients compared to controls (127 ± 33° vs. 156 ± 32°, p = 0.0024). The diameter, length and volume of the BA were significantly increased in LOPD patients compared to controls. 12/20 (60%) LOPD patients and 27/40 (68%) controls presented white matter lesions. During 5 years 2/9 LOPD patients developed an abnormal height of BA bifurcation according to the Smoker's criteria and in all patients the SUCA outlet angle decreased (138 ± 34° vs. 128 ± 32°, p = 0.019). One patient with prominent basilar dolichoectasia experienced a thalamic hemorrhage. CONCLUSION: Pompe disease is associated with BA dilation, elongation and elevated bifurcation height of the BA which might result in cerebrovascular complications. The SUCA outlet angle seems to be useful for monitoring the progression of BA dolichoectasia.

Long-term observation of incremental response and antibodies to voltage-gated calcium channels in patients with Lambert-Eaton myasthenic syndrome: two case reports.

INTRODUCTION: Lambert-Eaton myasthenic syndrome is a rare autoimmune disorder of neuromuscular transmission due to the presence of antibodies to presynaptic P/Q-type voltage-gated calcium channels. The gold standard of therapy is the potassium channel blocker 3,4-diaminopyridine. To the best of our knowledge, no clinical reports have been published to date about long-term follow-up outcomes in patients who discontinued 3,4-diaminopyridine therapy. In addition, we know of no recent articles in which the natural history in patients with autoimmune-mediated Lambert-Eaton myasthenic syndrome has been addressed. In this report, we describe the cases of two such patients. CASE PRESENTATION: Patient 1 was a Caucasian man who had been diagnosed at age 15 years with Lambert-Eaton myasthenic syndrome with symptoms of fluctuating muscle weakness and easy fatigability. These symptoms stabilized, and his electrophysiological parameters normalized, during treatment with a maintenance dose of 50mg/day of 3,4-diaminopyridine. After 5.5 years, however, he wished to discontinue the treatment. After that point, his electrophysiological parameters and presynaptic P/Q-type voltage-gated calcium-channel antibody titer remained stable. During the 15-year follow-up period, patient 1 reported mild exertion-induced complaints but did not feel restricted in his occupation and most daily activities. Patient 2 was a Caucasian man diagnosed at 32 years of age with a moderate limb girdle syndrome. He was treated with up to 80 mg/day of 3,4-diaminopyridine. Because of the drug's very short-lasting effect (<1 hour), however, he took it mostly irregularly (≤ 1 × 20 mg/day). During the 14- year period of observation, his repetitive nerve stimulation responses and presynaptic P/Q-type voltage-gated calcium-channel antibody titer remained stable, his compound muscle action potential amplitudes were decreasing and his clinical symptoms did not deteriorate. At his last follow-up examination, patient 2 was independent in all of his daily activities. CONCLUSION: Some patients with autoimmune-mediated Lambert-Eaton myasthenic syndrome show a stable clinical long-term course without treatment. The benefit of each long-term therapy should be critically assessed during follow-up, and possible side effects should be balanced against the quality of life in these patients.

Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy.

Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy.

Mitochondrial abnormalities in myofibrillar myopathies.

Histological mitochondrial changes are generally found to be associated with late onset myofibrillar myopathies (MFMs). How these changes contribute to the pathogenesis of MFMs is unknown. Mitochondrial changes, including COX-deficient fibers (n = 8), biochemical activities of respiratory chain complexes (n = 7), and multiple mtDNA deletions by long-range PCR (n = 9) were examined in patients with genetically confirmed MFMs [MYOT (n = 2), DES (n = 1), ZASP (n = 2), FLNC (n = 4)] and compared with age and sex matched normal controls (n = 27) and patients with a mitochondrial disorder with multiple mtDNA deletions due to nuclear genetic defects (n = 8). In 2 MFM patients, micro dissected fibers were analyzed for multiple mtDNA deletions by nested long-range PCR. The COX-deficient fibers only partly corresponded with fibers containing myofibrillar accumulations. In total, there was no difference in the percentage of COX-deficient fibers in MFM patients and normal controls. However, the percentage of COX-deficient fibers was significantly higher in 3 MFM patients. Two MFM patients but none of the controls had multiple mtDNA deletions. Nested long-range PCR detected multiple mtDNA deletions only in COX-deficient fibers. Citrate synthase activities in MFM patients were 1.5-fold increased by compared to those in controls, suggesting initiation of mitochondrial alterations. However, it is unclear whether this is a direct consequence of MFM pathology. *both authors contributed equally to the manuscript.

Respiratory function in late-onset Pompe disease patients receiving long-term enzyme replacement therapy for more than 48 months.

Respiratory impairment is the most important prognostic factor in patients with adult-onset Pompe disease. The effect of long-term enzyme replacement therapy (ERT) on pulmonary function remains unclear.Respiratory parameters (vital capacity (VCmax); forced expiratory volume (FEV1); peak expiratory flow (PEF); and blood gas analysis) were monitored every 6 months during a treatment period of 48-77 months of ERT in six patients with genetically and biochemically confirmed adult-onset Pompe disease. Postural drop of VCmax from sitting to supine position, maximal inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P0.1), and peak cough flow (PCF) were measured over a period of 12 months. Mean change to baseline were +8.8 % points for ΔVCmax, +6.2 % points for ΔFEV1, and +6.6 % points for ΔPEF after 48 months of ERT. In one patient, a decrease of respiratory parameters with later stabilization was observed under ERT until month 42, but noninvasive ventilation (NIV) had to be initiated due to nocturnal desaturation. In the final 12 months period, progressive diaphragm weakness was detected in 3/6 patients (median change in VC% drop +8 %).ERT seems to stabilize pulmonary function and may delay the requirement for ventilation in patients with late-onset Pompe disease.

Eosinophils in hereditary and inflammatory myopathies.

It is not known whether eosinophilic myositis is a specific histopathological feature of limb girdle muscular dystrophy 2A (LGMD2A). Number and location of eosinophils in skeletal muscle biopsies (n=100) was analysed by Giemsa and modified hematoxylin/eosin staining in patients with genetically confirmed myopathies (LGMD2A, LGMD2B, LGMD2L, facioscapulohumeral muscular dystrophy, dystrophinopathy), histologically confirmed idiopathic inflammatory myopathies (sporadic inclusion body myositis (sIBM), dermatomyositis (DM), polymyositis), amyotrophic lateral sclerosis (neurogenic control), and normal controls. The number of eosinophils/mm² was significantly higher in LGMD2A, PM, DM, and sIBM compared to controls but not significantly higher than other myopathies. A large overlap in the number of eosinophils/mm2 between all groups was seen. In all disease groups eosinophils were mainly found endomysially (46- 88%) and intra- and perivascularly (4-37%). There was no correlation between the numbers of eosinophils/mm² and (i) age at biopsy and (ii) the duration of the disease. The extent of myopathic, fibrotic, and inflammatory changes did not differ in samples with high and low eosinophil count. Eosinophils seem to represent an unspecific histological finding in hereditary and inflammatory myopathies, but also amyotrophic lateral sclerosis.