MRI in sarcoglycanopathies: a large international cohort study.

OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

SEPN1-related myopathy in three patients: novel mutations and diagnostic clues.

UNLABELLED: Mutations in SEPN1 cause selenoprotein N (SEPN)-related myopathy (SEPN-RM) characterized by early-onset axial and neck weakness, spinal rigidity, respiratory failure and histopathological features, ranging from mild dystrophic signs to a congenital myopathy pattern with myofibrillar disorganization. We report on clinical and instrumental features in three patients affected with a congenital myopathy characterized by prevalent neck weakness starting at different ages and mild myopathy, in whom we performed diagnosis of SEPN-RM. The patients presented myopathic signs since their first years of life, but the disease remained unrecognized because of a relatively benign myopathic course. In two cases, myopathic features were stable after 2 years of follow-up, but respiratory involvement worsened. The muscle MRI and muscle biopsy showed a typical pattern of SEPN-RM. Molecular diagnosis revealed two novel homozygous mutations in SEPN1, c.1176delA and c.726_727InsTCC. CONCLUSION: This report underlines the clinical diagnostic clues of early neck and axial weakness to suspect a SEPN-RM and the usefulness of muscle MRI in conjunction with clinical features to achieve the diagnosis. Our data confirm the slow progression of respiratory involvement in spite of the relatively stable course of myopathy. We report two previously undescribed mutations in SEPN1. WHAT IS KNOWN: • Mutations in SEPN1 cause myopathy characterized by early-onset axial and neck weakness spinal rigidity and respiratory failure. • SEPN-related myopathies have been initially associated with four distinct histopathological entities that however appear more mixed in recently described cases. What is New: • SEPN-related myopathies can remain unrecognized because of the normal early motor development and relatively benign myopathic course of the disease. • Our study adds two novel homozygous mutations to the number of reported pathogenic SEPN1 variants.

Primary central nervous system angiosarcoma: a case report and literature review.

Angiosarcoma is a rare vascular malignant neoplasm that mainly occurs in skin and soft tissues. Intracranial localization is very rare and only a few cases have been reported. This report intends to present the clinical, radiological and pathological pictures of a primary central nervous system angiosarcoma along with a review of the literature. A 35-year-old woman presented at our institution with weakness and sensory disturbances of her right hand. Neuroimaging revealed a roughly round, hemorrhagic and moderately enhancing lesion in the left frontal posterior region. The tumor was totally removed under awake anesthesia and continuous monitoring of motor and language functions. Histopathology revealed an epithelioid angiosarcoma. Radical removal, followed by adjuvant radiotherapy and chemotherapy, is able to completely control the disease for a relatively long period.

Imaging alterations in skeletal muscle channelopathies: a study in 15 patients.

Skeletal muscle channelopathies (SMC), including non dystrophic myotonias (NDM) and periodic paralyses (PP), are characterized by considerable clinical overlap and clinical features not always allow addressing molecular diagnosis. Muscle imaging has been shown to be useful for differential diagnosis in neuromuscular disorders, however it has been relatively poorly investigated in SMC. We studied 15 patients affected by genetically confirmed SMC (NDM = 9, PP = 6) through muscle MRI or CT of thighs and legs, including 11 patients mutated in SCN4A gene, 2 in CACNA1S and 2 in CLCN1. Mean age at muscle imaging was 45.2 ± 18 years (range 22-70). Overall, fatty infiltration was found in thigh muscles in 8 (53%) patients and in leg muscles in 10 (60%). All patients mutated in CLCN1 and CACNA1S had abnormal thigh and/or leg muscle MRI, regardless the disease duration. On the contrary normal thigh and leg muscle MRI or CT scans were observed in 4/15 (27%) patients, all mutated in SCN4A. Variable degrees of fatty changes were found in patients mutated in SCN4A, CACNA1S and CLCN1. No differences on overall score of fatty infiltration were detected between NDM and PP (p-value = 0.953) neither between presence or absence of permanent weakness (p-value = 0.951). Our data confirm the presence of muscle fatty changes in the majority of SMC patients, although without any specific pattern of involvement. However muscle MRI may be a useful tool for longitudinal follow-up of SMC patients, in particular to evaluate the occurrence and the progression of fixed myopathy.

Operability of glioblastomas: "sins of action" versus "sins of non-action".

Despite prognosis of glioblastomas is still poor, mounting evidence suggests that more extensive surgical resections are associated with longer life expectancy. However, the surgical indications, at present, are far from uniform and the concept of operability is extremely surgeon-dependant. The results of glioblastoma resection in 104 patients operated on between March 2005 and April 2011 were reviewed with the aim to shed some light on the limits between 'sins of action' (operating upon complex tumors causing a permanent severe deficit) and 'sins of non-action' (considering inoperable tumors that can be resected with good results). Fifty-five patients (54.4 %) (Group 1) presented with a 'disputable' surgical indication because of one or more of the following clinico-radiological aspects: involvement of motor and language areas (39.4 %), deep location (7.7 %), corpus callosum infiltration (13.4 %), or major vessels encasement (8.6 %). Forty-six (42.5 %) patients (Group 2) presented with an 'indisputable' surgical indication (readily accessible tumors in non-eloquent areas). Overall mortality was 2.9 %. The mean overall survival was 19.8 months and not significantly different in the two Groups (20.4 Group 2 and 19.5 months for Group 1; p = 0.7). Patients with GTR and <72 years had a longer survival (p = 0.004 and 0.03, respectively). Seventy patients (69.3 %) showed an uneventful post-operative course, without statistical significance difference between Group 1 and 2. The gross total removal of glioblastoma with many complexities (Group 1) was found to be feasible with acceptable mortality, morbidity and long-term survival rates.

Familial adult-onset Pompe disease associated with unusual clinical and histological features.

The adult-onset form of Pompe disease had a wide clinical spectrum, ranging from asymptomatic patients with increased CK to muscle cramps and pain syndrome or rigid-spine syndrome. In addition clinical severity and disease progression are greatly variable. We report on a family with 3 siblings characterized by an unusual adult-onset Pompe disease including dysphagia and weakness of tongue, axial and limb-girdle muscles, in association with atypical globular inclusions in muscle fibres. Our study confirms the great clinical and histological variability of adult-onset Pompe disease and further supports the need of careful evaluation of bulbar function in patients affected by this pathology.

Interdural haemorrhage of the posterior fossa due to infraclinoidal carotid artery aneurysm rupture.

Several anatomical studies indicate that the intracranial pachimeninges consist of two dural layers joined together, which divide while bordering the venous sinuses, therefore located in an interdural space. We present here an uncommon case of haematoma due to rupture of an infraclinoidal internal carotid artery aneurysm. The dome of the aneurysm leaned against the posterior wall of the cavernous sinus and, following laceration, pierced the inner dural layer and caused its detachment from the periosteal layer, thus determining a truly interdural haematoma which progressively involved the whole posterior fossa. A 42-year-old female was admitted to our institution with a recent history of thunderclap headache and right ophthalmoparesis. Two cerebral computerised scan tomographies performed elsewhere tested negative for subarachnoid haemorrhage. A cerebral magnetic resonance imaging (MRI) showed a thin collection of blood adjacent to the clivus and all along the wall of the posterior fossa and foramen magnum. A right infraclinoid internal carotid artery aneurysm was also diagnosed, subsequently better highlighted on angiography. The patient underwent surgery with aneurysm clipping. Post-operative course was uneventful, and control angiography showed complete exclusion of the aneurysm from blood circulation. The patient was discharged 5 days later. At 3 months follow-up ophthalmoplegia had disappeared, and the patient had fully recovered. The possibility of a truly interdural location, particularly in cases of non-traumatic parasellar or clival haematomas, must be included in the differential diagnosis of posterior fossa extra-axial haemorrhages. MRI is the test of choice for diagnostic purposes.

A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype.

Presenilin mutations are the main cause of familial Alzheimer's disease. So far, more than 160 mutations in the Presenilin 1 gene (PSEN1) and approximately 10 mutations in the homologous Presenilin 2 gene (PSEN2) have been identified. Some PSEN1 mutations are associated with a phenotype fulfilling the clinical criteria of frontotemporal dementia. In PSEN2, T122P and M239V mutations presented with severe behavioral disturbances. We describe an Italian patient with a novel PSEN2 mutation (Y231C) who showed behavioral abnormalities and language impairment as presenting symptoms, with later involvement of other cognitive abilities, particularly of posterior functions.

Fatal Aspergillus brain abscess in immunocompetent patient.

Intracranial aspergillosis is a rare pathologic condition, difficult to treat and often fatal which generally affects immunocompromised hosts. High-dose steroid therapy represents a risk factor for opportunistic infections. We report a case of fatal brain abscess in an immunocompetent patient with a previous diagnosis of acute disseminated encephalomyelitis (ADEM) in whom a high-dose steroid course has probably contributed to the development of the fungal infection. Despite steroids' relative safety, clinicians must remain alert to potential fatal complication that could arise from their use.

Functional MRI in malformations of cortical development: activation of dysplastic tissue and functional reorganization.

BACKGROUND AND PURPOSE: Functional neuroimaging and electrophysiological studies suggest that dysplastic neural tissue in malformations of cortical development may participate in task performance, and that functional organization can be altered beyond visible lesion boundaries. The aim of this work was to investigate cortical function in a heterogeneous group of patients with malformations of cortical development. METHODS: Twelve patients participated in the study, 2 for each of the following categories: subcortical, periventricular, and band heterotopia, unilateral and bilateral polymicrogyria, and focal cortical dysplasia. Functional magnetic resonance imaging was performed with finger tapping, somatosensory and visual stimulation, and language-related tasks. RESULTS: We found activations within the dysplastic tissue in subcortical heterotopia, band heterotopia, and polymicrogyria, but not in periventricular heterotopic nodules. In one of the patients with focal cortical dysplasia, language-related activation involved part of the lesion. Functional reorganization beyond visible lesion boundaries was seen, with different patterns, in 4 patients. CONCLUSIONS: In accordance with previous reports, our findings indicate that dysplastic neural tissue can be activated during task performance, and that in some patients, extensive functional reorganization occurs, highlighting the importance of functional magnetic resonance imaging in presurgical planning in those patients for whom epilepsy surgery is considered as an option.

Biexponential and diffusional kurtosis imaging, and generalised diffusion-tensor imaging (GDTI) with rank-4 tensors: a study in a group of healthy subjects.

OBJECT: Clinical diffusion imaging is based on two assumptions of limited validity: that the radial projections of the diffusion propagator are Gaussian, and that a single directional diffusivity maximum exists in each voxel. The former can be removed using the biexponential and diffusional kurtosis models, the latter using generalised diffusion-tensor imaging. This study provides normative data for these three models. MATERIALS AND METHODS: Eighteen healthy subjects were imaged. Maps of the biexponential parameters D (fast), D (slow) and f (slow), of D and K from the diffusional kurtosis model, and of diffusivity D' were obtained. Maps of generalised anisotropy (GA) and scaled entropy(SE) were also generated, for second and fourth rank tensors. Normative values were obtained for 26 regions. RESULTS: In grey versus white matter, D (slow) and D' were higher and D (fast), f (slow) and K were lower. With respect to maps of D', anatomical contrast was stronger in maps of D (slow) and K. Elevating tensor rank increased SE, generally more significantly than GA, in: anterior limb of internal capsule, corpus callosum, deep frontal and subcortical white matter, along superior longitudinal fasciculus and cingulum. CONCLUSION: The values reported herein can be used for reference in future studies and in clinical settings.

Surgifoam and mitoxantrone in the glioblastoma multiforme postresection cavity: the first step of locoregional chemotherapy through an ad hoc-placed catheter: technical note.

OBJECTIVE: To investigate the safety and feasibility of a novel form of treatment offered by the direct intraoperative application of a Surgifoam-mitoxantrone mix into a glioblastoma multiforme postresection cavity. A technique for the placement of an intracavity catheter connected with a subcutaneous reservoir for further locoregional mitoxantrone administration is also described. METHODS: Between January and December 2004, 22 consecutive recurrent glioblastoma multiforme patients (14 men, 8 women; age, 56-72 yr; average, 64 yr; median, 65 yr) were enrolled in this study. All patients underwent image-assisted gross total resection of the pathological tissue. A Surgifoam-mitoxantrone mix (1 g Surgifoam powder, 3 ml physiological solution, and 12 mg mitoxantrone in 6 ml) was used to fill the surgical cavity. A ventricular catheter, connected to a Rickham subcutaneous reservoir, was then positioned in the surgical cavity for future mitoxantrone administration. RESULTS: Toxic effects caused by mitoxantrone administration were not observed in any patients during the first postoperative month. On postoperative Days 1, 7, and 30, computed tomographic scans excluded surgical complications. In three patients, residual tumor was disclosed. CONCLUSION: A mix of Surgifoam and mitoxantrone could be safely applied intraoperatively into the post-glioblastoma multiforme resection cavity without any observable side effects. This technique may benefit both the surgeon and the patient by taking advantage of the drug's hemostatic and cytostatic properties.

Craniotomy using image-guided oscillating saw: technical note.

OBJECTIVE: To describe a new craniotomic technique that eliminates burr holes and minimizes bone loss along the craniotomic line. PATIENTS AND METHODS: Fifty burr hole free craniotomies were performed in varied locations using an image-guided micro-oscillating saw. Care was taken to avoid cutting the inner cortical layer. Upon completing the micro-oscillating saw cut the inner table could then be gently fractured along the craniotomic line with a thin bladed osteotome. Simple silk sutures were used to resecure the bone flap. RESULTS: The craniotomic time required for this procedure ranged from 7 to 24 minutes (mean: 13 minutes). We observed no dural lacerations or signs of brain damage in any of these procedures. The use of image guidance allows a continuous measure of bone thickness along the craniotomic line. In all of the cases we report the cosmetic result was excellent. CONCLUSION: This alternative technique of craniotomy can be used in selected cases to achieve excellent cosmetic results which avoid the time and cost of complex reconstruction techniques.

Stimulation of the globus pallidus internus for childhood-onset dystonia.

We report the results of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 12 patients with childhood-onset generalized dystonia refractory to medication, including 3 patients with status dystonicus. There were 8 patients who had DYT1-negative primary dystonia, 1 had DYT1-positive dystonia, and 3 had symptomatic dystonia. Stimulation was effective in all but 1 patient. Dystonic postures and movements of the axis and limbs responded to DBS to a greater extent than oromandibular dystonia and fixed dystonic postures. These findings provide further evidence that pallidal stimulation is an effective treatment for intractable childhood-onset dystonia, including status dystonicus, and together with previous findings, suggest that it should be considered the treatment of choice for these conditions.

A simple method to assess accuracy of deep brain stimulation electrode placement: pre-operative stereotactic CT + postoperative MR image fusion.

OBJECTIVE: To describe a method for the measurement of the accuracy of deep brain stimulation (DBS) electrode placement with the use of image fusion technologies. PATIENTS AND METHODS: Ten consecutive patients suffering from movement disorders underwent DBS electrode placement. Postoperative MR images were fused with the pre-operative stereotactic CT. The placement error in the anteroposterior, lateral and vertical planes was calculated. RESULTS: The anteroposterior mean error +/- SD was 0.61 +/- 0.22 mm (range 0.2-0.9 mm). The lateral mean error +/- SD was 0.65 +/- 0.27 mm (range 0.2-2.2 mm). The vertical mean error +/- SD was 0.82 +/- 0.31 mm (range 0.3-1.6 mm). CONCLUSIONS: This technique provides a simple and precise method for the evaluation of the accuracy of DBS electrode placement.

Phase II trial of cisplatin plus temozolomide, in recurrent and progressive malignant glioma patients.

We report a phase II trial of cisplatinum and temozolomide (TMZ) combination in recurrent malignant glioma patients. The DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGAT) is important in glioblastoma resistance to alkylating antitumor agents. In vitro, cisplatin (CDDP) decreases MGMT activity in a time- and dose-dependent manner. Thirty-three recurrent malignant glioma patients (20 GBM-13 AA) were treated at recurrence or progression with a CDDP and TMZ association. On days 1 and 2, iv CDDP (40 mg/sqm) was administered. TMZ (at the dose of 200 mg/sqm) was administered as a single oral daily-dose on days 2-6 (starting 24 h after the first CDDP dose), the cycle was repeated every 4 weeks. All patients had been previously treated with surgery followed by radiotherapy and CDDP + BCNU chemotherapy. The primary endpoint of the study was progression free survival at 6 months (PFS-6). Secondary endpoints included radiological response and toxicities. Thirty-three patients received a total of 113 courses (median 3 range 1-11). Complete responses were not observed, partial responses were 18.8% with an additional 39.9% of stable disease. For the whole group of patients the PFS at 6 and 12 months was 52% and 15% with a median TTP of 33 weeks. PFS-6 for GBM and Anaplastic astrocytoma (AA) were 35% and 69%, respectively. PFS-12 for GBM and AA were 13.8% and 17.3%, respectively. Median TTP was 21.3 and 39.5 weeks, respectively. The principal toxic effects of the regimen were: neutropenia (5 WHO grade IV), thrombocytopenia (4 WHO grade IV), nausea and vomiting.