Characterization of patients with Becker muscular dystrophy by histology, magnetic resonance imaging, function, and strength assessments.

INTRODUCTION/AIMS: Becker muscular dystrophy (BMD) is characterized by variable disease severity and progression, prompting the identification of biomarkers for clinical trials. We used data from an ongoing phase II study to provide a comprehensive characterization of a cohort of patients with BMD, and to assess correlations between histological and magnetic resonance imaging (MRI) markers with muscle function and strength. METHODS: Eligible patients were ambulatory males with BMD, aged 18 to 65 years (200 to 450 meters on 6-minute walk test). The following data were obtained: function test results, strength, fat-fraction quantification using chemical shift-encoded MRI (whole thigh and quadriceps), and fibrosis and muscle fiber area (MFA) of the brachial biceps. RESULTS: Of 70 patients screened, 51 entered the study. There was substantial heterogeneity between patients in muscle morphology (histology and MRI), with high fat replacement. Total fibrosis correlated significantly and mostly moderately with all functional endpoints, including both upper arm strength assessments (left and right elbow flexion rho -.574 and -.588, respectively [both P < .0001]), as did MRI fat fraction (whole thigh and quadriceps), for example, with four-stair-climb velocity -.554 and -.550, respectively (both P < .0001). Total fibrosis correlated significantly and moderately with both MRI fat fraction assessments (.500 [P = .0003] and .423 [.0024], respectively). DISCUSSION: In this BMD cohort, micro- and macroscopic morphological muscle parameters correlated moderately with each other and with functional parameters, potentially supporting the use of MRI fat fraction and histology as surrogate outcome measures in patients with BMD, although additional research is required to validate this.

Diffusion tensor imaging reveals subclinical alterations in muscles of patients with Becker muscular dystrophy.

OBJECTIVES: Becker muscular dystrophy (BMD) is a relatively less investigated neuromuscular disease, partially overlapping the phenotype of Duchenne dystrophy (DMD). Physiopathological and anatomical patterns are still not comprehensively known, despite recent effort in the search of early biomarkers. Aim of this study was to selectively compare normal appearing muscles of BMD with healthy controls. METHODS: Among a pool of 40 BMD patients and 20 healthy controls, Sartorius and gracilis muscles were selected on the basis of a blinded clinical quantitative/qualitative evaluation, if classified as normal (0 or 1 on Mercuri scale) and subsequently segmented on diffusion tensor MRI scans with a tractographic approach. Diffusion derived parameters were extracted. RESULTS: Non-parametric testing revealed significant differences between normal and normal appearing BMD derived parameters in both muscles, the difference being more evident in sartorius. Bonferroni-corrected P-values (<.05) of Mann-Whitney test could discriminate between BMD and controls for standard deviation of all diffusion parameters (mean diffusivity, fractional anisotropy, axial and radial diffusivity) in both sartorius and gracilis, while in sartorius the significant difference was found also in the average values of the same parameters (with exception of RD). CONCLUSIONS: This method could identify microstructural alterations in BMD normal appearing sartorius and gracilis. ADVANCES IN KNOWLEDGE: Diffusion based MRI could be able to identify possible early or subclinical microstructural alterations in dystrophic patients with BMD.

Diabetic ketoacidosis with central nervous system involvement: Conventional and advanced magnetic resonance neuroimaging findings.

Diabetic ketoacidosis (DKA) is a serious complication in children with diabetes mellitus type 1 (DM1). In rare and severe cases DKA may be complicated by cerebral edema, central brain herniation and cerebral infarctions. We present the magnetic resonance imaging findings in a child with DKA and central nervous system involvement; diffusion tensor imaging (DTI) and functional MRI (fMRI) were performed to assess the white matter integrity of sensory pathways and cortical sensory processing. Conventional imaging showed bilateral uncal herniation, effacement of the perimesencephalic cisterns, wide ischemic lesions in the posterior cerebral artery (PCA) territories, sagging brainstem and Duret's hemorrhage consistent with signs of central brain herniation and intracranial hypertension. Advanced MRI showed a possible left-sided cortical reorganization for sensory function, with underlying left cortico-talamic and cortico-spinal pathways less severely impaired. Knowledge of the full framework in these conditions is of vital importance for timely patient management; advanced neuroimaging techniques may be considered as prognostic indicators in those cases with extensive involvement of eloquent brain areas.

The CONNECT project: Combining macro- and micro-structure.

In recent years, diffusion MRI has become an extremely important tool for studying the morphology of living brain tissue, as it provides unique insights into both its macrostructure and microstructure. Recent applications of diffusion MRI aimed to characterize the structural connectome using tractography to infer connectivity between brain regions. In parallel to the development of tractography, additional diffusion MRI based frameworks (CHARMED, AxCaliber, ActiveAx) were developed enabling the extraction of a multitude of micro-structural parameters (axon diameter distribution, mean axonal diameter and axonal density). This unique insight into both tissue microstructure and connectivity has enormous potential value in understanding the structure and organization of the brain as well as providing unique insights to abnormalities that underpin disease states. The CONNECT (Consortium Of Neuroimagers for the Non-invasive Exploration of brain Connectivity and Tracts) project aimed to combine tractography and micro-structural measures of the living human brain in order to obtain a better estimate of the connectome, while also striving to extend validation of these measurements. This paper summarizes the project and describes the perspective of using micro-structural measures to study the connectome.

Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study.

Objective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD. Methods: Males aged 18-65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations. Results: Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat-placebo differences at Month 12 of -1.35% (p = 0.0149) and -1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo. Conclusion: The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.

In medication-overuse headache, fMRI shows long-lasting dysfunction in midbrain areas.

OBJECTIVE: The primary aim of our study was to evaluate if a group of medication-overuse headache (MOH) patients present dysfunctions in the mesocorticolimbic dopamine circuit. The secondary aim was to disentangle the role of the medication overuse and of the acute/chronic headache in determining these alterations and to investigate their persistence. BACKGROUND: Several researches have suggested that MOH may belong to the spectrum of addictive behavior. Preclinical models and neuroimaging studies have consistently demonstrated that in addiction, critical long-lasting alterations occur in the mesocorticolimbic dopamine circuit. If MOH shares some neurophysiological features with addiction, long-lasting functional alterations of the mesocorticolimbic dopamine system related to medication overuse should be present. METHODS: We collected functional magnetic resonance imaging data during the execution of a decision-making under risk paradigm in 8 MOH patients immediately after beginning medication withdrawal, in 8 detoxified MOH patients at 6 months after beginning medication withdrawal, in 8 chronic migraine patients, and in 8 control subjects. RESULTS: Our results revealed that MOH patients present: (1) reduced task-related activity in the substantia nigra/ventral tegmental area complex and increased activity in the ventromedial prefrontal cortex, when compared with controls; (2) reduced activity in the substantia nigra/ventral tegmental area complex, when compared with chronic migraine patients; (3) increased activity in the ventromedial prefrontal cortex, when compared with detoxified MOH patients. CONCLUSION: Our study showed that MOH patients present dysfunctions in the mesocorticolimbic dopamine circuit, in particular in the ventromedial prefrontal cortex and in the substantia nigra/ventral tegmental area complex. The ventromedial prefrontal cortex dysfunctions seem to be reversible and attributable to the acute/chronic headache, whereas the substantia nigra/ventral tegmental area complex dysfunctions are persistent and possibly related to medication overuse. These dysfunctions might be the expression of long-lasting neuroadaptations related to the overuse of medications and/or a pre-existing neurophysiological condition leading to vulnerability to medication overuse. The observed persistent dysfunctions in the midbrain dopamine suggest that MOH may share some neurophysiological features with addiction.

Interhemispherical Anatomical Disconnection in Disorders of Consciousness Patients.

In patients with disorder of consciousness (DOC), the corpus callosum (CC) and subcortical white matter (SWM) integrity were shown to discriminate between diagnostic categories. The aims of the study were: (1) to clarify the link between the integrity of CC and of SWM and the clinical status in DOC patients, disentangling the role played by the different brain injuries (traumatic or hemorrhagic brain injury); (2) to investigate the relationship between the CC integrity and the brain metabolism. We assessed the diagnostic accuracy of the CC and SWM integrity, using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (sMRI), in a sample of DOC individuals, well balanced for diagnosis and etiology. The CC DTI-derived measures were correlated with the brain metabolism, computed with fluorodeoxyglucose positron emission tomography. Our results showed that the CC macrostructural DTI-derived measures discriminate between diagnosis and correlate with the clinical status of DOC patients irrespective of the etiology. Moreover, the CC DTI-derived measures strongly correlate with the metabolism of the right hemisphere. No significant diagnostic accuracy emerged for the CC sMRI evaluation and the SWM measures. Our results indicate that: (1) the degree of the interhemispherical anatomical disconnection is a marker of the level of consciousness independent from the type of brain injury; (2) CC alterations might be the consequence of the reduced brain metabolism. Remarkably, our results suggest that the functional interplay between the two hemispheres is linked tightly to the level of consciousness.

Ultrasound guided mini-invasive tailored approach and intraoperative neurophysiological monitoring: a synergistic strategy for the removal of tumors near the motor cortex. A preliminary experience.

BACKGROUND: The aim of this paper was to evaluate the synergic strategy comprising intraoperative neurophysiological monitoring and ultrasound sonography in terms of clinical motor scores and extent of resection. METHODS: Patients harboring tumors in close relationship with the motor cortex were operated on with image-guided mini-invasive approach and multimodal neurophysiological monitoring. The peculiarity is the partial exposure of the motor cortex and the limited electrophysiological mapping used to search for negative spots. Multimodal neurophysiological monitoring comprised the electrocortical stimulation, somatosensory evoked potentials, motor evoked potentials and subcortical stimulation. Ultrasound sonography guided the tumor removal. The post-op clinical motor scores and the extent of resection were assessed. RESULTS: Twelve patients were operated on with the combined approach and were further analyzed. Six had high grade gliomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma and three had metastasis. One out of 12 had a worsening of the motor scores at the last follow-up. The mean extent of resection was 90% ranging from 60% to 100%, but in 9 out of 12 patients, it reached or exceeded 90%. CONCLUSIONS: The synergic strategy comprising intraoperative multimodal neurophysiological monitoring and the ultrasound sonography is feasible in all surgeries. Data are promising in terms of both clinical motor scores and extent of resection. This strategy represents an alternative approach to the treatment of supratentorial tumors, although further studies are necessary to confirm the long-term efficacy of this procedure.

In vivo DTI tractography of the rat brain: an atlas of the main tracts in Paxinos space with histological comparison.

Diffusion tensor imaging (DTI) is a magnetic resonance modality that permits to characterize the orientation and integrity of white matter (WM). DTI-based tractography techniques, allowing the virtual reconstruction of WM tract pathways, have found wide application in preclinical neurological research. Recently, anatomically detailed rat brain atlases including DTI data were constructed from ex vivo DTI images, but tractographic atlases of normal rats in vivo are still lacking. We propose here a probabilistic tractographic atlas of the main WM tracts in the healthy rat brain based on in vivo DTI acquisition. Our study was carried out on 10 adult female Sprague-Dawley rats using a 7T preclinical scanner. The MRI protocol permitted a reliable reconstruction of the main rat brain bundles: corpus callosum, cingulum, external capsule, internal capsule, anterior commissure, optic tract. The reconstructed fibers were compared with histological data, proving the viability of in vivo DTI tractography in the rat brain with the proposed acquisition and processing protocol. All the data were registered to a rat brain template in the coordinate system of the commonly used atlas by Paxinos and Watson; then the individual tracts were binarized and averaged, obtaining a probabilistic atlas in Paxinos-Watson space of the main rat brain WM bundles. With respect to the recent high-resolution MRI atlases, the resulting tractographic atlas, available online, provides complementary information about the average anatomical position of the considered WM tracts and their variability between normal animals. Furthermore, reference values for the main DTI-derived parameters, mean diffusivity and fractional anisotropy, were provided. Both these results can be used as references in preclinical studies on pathological rat models involving potential alterations of WM.

The lateral infratrigeminal transpontine window to deep pontine lesions.

OBJECT: Surgery of brainstem lesions is increasingly performed despite the fact that surgical indications and techniques continue to be debated. The deep pons, in particular, continues to be a critical area in which the specific risks related to different surgical strategies continue to be examined. With the intention of bringing new knowledge into this important arena, the authors systematically examined the results of brainstem surgeries that have been performed through the lateral infratrigeminal transpontine window. METHODS: Between 1990 and 2013, 29 consecutive patients underwent surgery through this window for either biopsy sampling or for removal of a deep pontine lesion. All of this work was performed at the Department of Neurosurgery of the Istituto Nazionale Neurologico "Carlo Besta", in Milan, Italy. A retrospective analysis of the findings was conducted with the intention of bringing further clarity to this important surgical strategy. RESULTS: The lateral infratrigeminal transpontine window was exposed through 4 different approaches: 1) classic retrosigmoid (15 cases), 2) minimally invasive keyhole retrosigmoid (10 cases), 3) translabyrinthine (1 case), and 4) combined petrosal (3 cases). No deaths occurred during the entire clinical study. The surgical complications that were observed included hydrocephalus (2 cases) and CSF leakage (1 case). In 6 (20.7%) of 29 patients the authors encountered new neurological deficits during the immediate postoperative period. All 6 of these patients had undergone lesion removal. In only 2 of these 6 patients were permanent sequelae observed at 3 months follow-up. These findings show that 93% of the patients studied did not report any permanent worsening of their neurological condition after this surgical intervention. CONCLUSIONS: This retrospective study supports the idea that the lateral infratrigeminal transpontine window is both a low-risk and safe corridor for either biopsy sampling or for removal of deep pontine lesions.

Aphasia induced by gliomas growing in the ventrolateral frontal region: assessment with diffusion MR tractography, functional MR imaging and neuropsychology.

INTRODUCTION: Lesions in the ventrolateral region of the dominant frontal lobe have been historically associated with aphasia. Recent imaging results suggest that frontal language regions extend beyond classically defined Broca's area to include the ventral precentral gyrus (VPCG) and the arcuate fasciculus (AF). Frontal gliomas offer a unique opportunity to identify structures that are essential for speech production. The aim of this prospective study was to investigate the correlation between language deficits and lesion location in patients with gliomas. METHODS: Nineteen patients with glioma and 10 healthy subjects were evaluated with diffusion tensor imaging magnetic resonance (MR) tractography, functional MR (verb generation task) and the Aachener Aphasie Test. Patients were divided into two groups according to lesion location with respect to the ventral precentral sulcus: (i) anterior (n=8) with glioma growing in the inferior frontal gyrus (IFG) and underlying white matter; (ii) posterior (n=11) with glioma growing in the VPCG and underlying white matter. Virtual dissection of the AF, frontal intralobar tract, uncinate fasciculus (UF) and inferior frontal occipital fasciculus (IFOF) was performed with a deterministic approach. RESULTS: Seven posterior patients showed aphasia classified as conduction (4), Broca (1), transcortical motor (1) and an isolated deficit of semantic fluency; one anterior patient had transcortical mixed aphasia. All posterior patients had invasion of the VPCG, however only patients with aphasia had also lesion extension to the AF as demonstrated by tractography dissections. All patients with language deficits had high grade glioma. Groups did not differ regarding tumour volume. A functional pars opercularis was identified with functional MR imaging (fMRI) in 17 patients. CONCLUSIONS: Gliomas growing in the left VPCG are much more likely to cause speech deficits than gliomas infiltrating the IFG, including Broca's area. Lesion extension to the AF connecting frontal to parietal and temporal regions is an important mechanism for the appearance of aphasia.