Federica Montagnese

Orbiting around the orbital myositis: clinical features, differential diagnosis and therapy

Orbital myositis (OM) is a rare disease whose clinical heterogeneity and different treatment options represent a diagnostic and therapeutic challenge. We aim to review the state of knowledge on OM, also describing a cohort of patients diagnosed in our centre, to highlight some remarkable clinical features. A literature review was conducted in PubMed and Medline databases. The herein described cohort is composed of seven OM patients, diagnosed according to clinical, laboratory and neuroradiological features, whose clinical data were retrospectively analysed. OM is a non-infectious, inflammatory process primarily involving extraocular eye-muscles. It typically presents as an acute to sub-acute, painful ophthalmoplegia with signs of ocular inflammation, but atypical cases without pain or with a chronic progression have been described. The wide range of OM mimicking diseases make a prompt diagnosis challenging but orbit MRI provides valuable clues for differential diagnosis. Timely treatment is greatly important as OM promptly responds to steroids; nevertheless, partial recovery or relapses often occur. In refractory, recurrent or steroid-intolerant cases other therapeutic options (radiotherapy, immunosuppressants, immunoglobulins) can be adopted, but the most effective therapeutic management is yet to be established. In this review, we provide a detailed clinical description of OM, considering the main differential diagnoses and suggesting the most useful investigations. In light of the currently available data on therapy efficacy, we propose a therapeutic algorithm that may guide neurologists in OM patients’ management.

Clinical and pathophysiological clues of respiratory dysfunction in late-onset Pompe disease: New insights from a comparative study by MRI and respiratory function assessment

Respiratory insufficiency commonly develops in patients with Late Onset Pompe Disease (LOPD). It is conceivable that a timely starting of enzyme replacement therapy could avoid this life-threatening complication. Respiratory function in LOPD is commonly evaluated with standard pulmonary tests which do not extensively provide an accurate definition of the muscular pathophysiology. In eleven patients with LOPD and five healthy subjects, we compared pulmonary function results with MRI data, based on scans of the right lung acquired on maximum expiration and inspiration. We observed that variations in the cranio-caudal lung height and of lung areas in inspiration and expiration (lung delta) as well as the area of diaphragmatic movement strongly correlated with pulmonary function results. Moreover, MRI data confirmed that development of respiratory insufficiency in LOPD is mainly due to the diaphragmatic weakness with sparing of the antero-posterior chest expansion related to the activity of the intercostal muscles. These results suggest that respiratory muscle MRI is a quick, useful and reproducible tool for patient management as well as a reliable outcome measure for future LOPD therapeutic trials.

Sporadic late-onset nemaline myopathy in a woman with multiple myeloma successfully treated with lenalidomide/dexamethasone

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Two patients with GMPPB mutation: the overlapping phenotypes of limb-girdle myasthenic syndrome and limb-girdle muscular dystrophy dystroglycanopathy

Mutations in the guanosine diphosphate–mannose pyrophosphorylase‐B gene (GMPPB) have been identified in congenital muscular dystrophies, limb‐girdle muscular dystrophy (LGMD2T), and congenital myasthenic syndromes (CMSs); overall, 41 patients have been described.

Two patients with GMPPB mutation: the overlapping phenotypes of limb‐girdle myasthenic syndrome and LGMD2T dystroglycanopathy

Mutations in the guanosine diphosphate–mannose pyrophosphorylase‐B gene (GMPPB) have been identified in congenital muscular dystrophies, limb‐girdle muscular dystrophy (LGMD2T), and congenital myasthenic syndromes (CMSs); overall, 41 patients have been described.

Acute parkinsonism as first manifestation of systemic lupus erythematosus unmasked by CMV infection.

A 46-year-old Romanian woman was hospitalized because of 1-month history of balance and gait disturbances, slowness of movements, frequent falls and urinary incontinence. There was no family history of movement disorders or other neurological or psychiatric diseases. Exposure to toxic substances, illicit drugs or dopamine receptors blocking agents was denied. Neurological examination at admission (video, segment A) revealed short-step gait with need of assistance to walk, freezing of gait and postural instability; there was facial hypomimia, increased blinking, marked neck and generalized limb rigidity and bradykinesia, dystonic posturing of the right foot and ideomotor apraxia. She also showed paralysis of the left third cranial nerve with ocular ptosis and divergent strabismus, motor impersistence of the tongue, hyperreflexia and extensor plantar responses. Motor Unified Parkinson’s disease rating scale (UPDRS) was 45/108. Laboratory examination highlighted: anaemia (erythrocytes = 3,250,000/mmc; haemoglobin = 9.9 g/dl); leucopoenia (leukocytes = 4,000/mmc); proteinuria [proteinuria/ 24 h = 34 mg/dl (normal values, n.v. \12 mg/dl); Bence Jones proteinuria = 71 mg/dl (n.v. \50 mg/dl)]; ANA = 1:640 (n.v. \1:40); ENA Sm = 304.4 EU/ml (n.v. 0.0–25.0); ENA Sm-RNP = 167.2 EU/ml (n.v. 0–25); hypocomplementemia [C3 = 48 mg/dl (n.v. 90–180 mg/ dl), C4 = 7 mg/dl (v.n. 10–40 mg/dl)]; positive Ab anticardiolipin [IgG = 39.5 GPL (n.v. 0–10), IgM = 16.4 GPL (n.v. 0–8)]. Ab anti-HIV, anti-Treponema pallidum and antiBorrelia burgdorferi were negative. Brain MRI showed high-intensity signal in T2-weighted images and FLAIR of white matter at semioval centres, periventricular region and internal capsule on both sides of the brain. SPECT imaging of the dopamine transporter was normal (Fig. 1). Cephalorachidian fluid (CSF) analysis disclosed normal proteins, glucose, absence of cells and of oligoclonal bands. Determination of virus-specific antibodies in liquor revealed increase IgM ([32.9 U/ml; v.n. Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1844-z) contains supplementary material, which is available to authorized users.

Intracranial Arterial Abnormalities in Patients with Late-Onset Pompe Disease

Background and objectives Pompe disease is a rare metabolic disorder due to lysosomal alpha-glucosidase (GAA) deficiency. It is considered as a multi-systemic disease since, although glycogen accumulation is largely prominent in heart, skeletal and respiratory muscles, other organs can also be affected. As regards the vascular system, few reports have documented cerebrovascular malformations in Pompe patients. The aim of this studywas to define the presence and type of intracranial arterial abnormalities in a cohort of late onset Pompe disease (LOPD) patients. Methods We have studied 21 LOPD patients with cerebral CT angiography (CTA), using maximum intensity projection and volume rendering technique for 3D-image reconstruction. Results We found intracranial arterial abnormalities in 13/21 patients (62 %), of whom: 2/21 patients (9.5 %) showed an unruptured intracranial aneurysm (respectively 2 and 4 mm), 10/21 (47 %) had a vertebrobasilar dolichoectasia (VBD) and 1/21 a basilar artery fenestration. Signs of lacunar encephalopathy (insular, capsular and frontal subcortical lesions) were detected in 13/21 patients (62 %) and this correlated with the presence of respiratory impairment (p=0.017). Conclusions These findings differ from what has been previously observed in healthy, aged-matched populations and confirm that cerebral arteries abnormalities, mainly involving the posterior circle, are not so rare in LOPD patients and are often accompanied by a lacunar encephalopathy that might represent a hypoxic-ischemic origin. A CTA or an MRA is recommended, in LOPD patients, for early detection of cerebrovascular malformations as they could lead to life-threatening events such as sub-arachnoid haemorrhage or brainstem compression.

T.P.16

Pompe disease is a rare metabolic myopathy due to mutations in the gene encoding acid alpha-glucosidase (GAA) involved in glycogen degradation. Two clinical presentations can occur: infantile form and late-onset form. Herein, we describe a cohort of 33 late-onset Pompe disease (LOPD) patients diagnosed at our centre from 1997 to date. Our aim is to present clinical and functional data collected in this long time lapse and to describe unusual clinical and genetic features. LOPD diagnosis was made with muscle GAA residual activity assay and GAA sequence analysis. At follow-up patients underwent motor, respiratory, cardiac and muscle MRI evaluations. Motor performances were tested with Walton Gardner-Medwin, MRC, GSGC, 6MWT. Respiratory function was assessed through FVC% in upright and supine position 19 males, 14 females. The onset symptom was asymptomatic hyperckemia in 13 patients (39%), proximal weakness in 19 (57%) and respiratory failure in 1 (3%). Atypical clinical features were observed in 4 patients: a 66year-old female with a severe distal muscle weakness; a 70-year-old male with mesial temporal sclerosis; a 46-years-old male with severe hearing loss and a 52-year-old male with leukoencephalopathy. The median age at diagnosis was 38years, median diagnostic delay 8.3years. GAA sequence analysis showed the common IVS1–13T>G mutation in all patients associated, in 25 patients, with a second mutation. Two brothers were IVS1–13T>G homozygous and 1 patient had a new mutation (c.2395C>G). In the remaining 8 no second mutation was found. 17 patients started enzyme replacement therapy (ERT). Our study confirms LOPD clinical and genetic heterogeneity. The atypical features encountered may contribute to expand the clinical aspects of the disease highlighting its multisystemic nature. Early diagnosis allows, when indicated, earlier ERT initiation even if, in our cohort, treatment responses were variable and not clearly correlated with diagnostic delay.

Thigh muscle segmentation of chemical shift encoding-based water-fat magnetic resonance images: The reference database MyoSegmenTUM

Magnetic resonance imaging (MRI) can non-invasively assess muscle anatomy, exercise effects and pathologies with different underlying causes such as neuromuscular diseases (NMD). Quantitative MRI including fat fraction mapping using chemical shift encoding-based water-fat MRI has emerged for reliable determination of muscle volume and fat composition. The data analysis of water-fat images requires segmentation of the different muscles which has been mainly performed manually in the past and is a very time consuming process, currently limiting the clinical applicability. An automatization of the segmentation process would lead to a more time-efficient analysis. In the present work, the manually segmented thigh magnetic resonance imaging database MyoSegmenTUM is presented. It hosts water-fat MR images of both thighs of 15 healthy subjects and 4 patients with NMD with a voxel size of 3.2x2x4 mm3 with the corresponding segmentation masks for four functional muscle groups: quadriceps femoris, sartorius, gracilis, hamstrings. The database is freely accessible online at https://osf.io/svwa7/?view_only=c2c980c17b3a40fca35d088a3cdd83e2. The database is mainly meant as ground truth which can be used as training and test dataset for automatic muscle segmentation algorithms. The segmentation allows extraction of muscle cross sectional area (CSA) and volume. Proton density fat fraction (PDFF) of the defined muscle groups from the corresponding images and quadriceps muscle strength measurements/neurological muscle strength rating can be used for benchmarking purposes.

Core Clinical Phenotypes in Myotonic Dystrophies

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled “Beyond Borders: Myotonic Dystrophies—A European Perception.”