Concomitant diagnosis of multiple sclerosis and human immunodeficiency virus (HIV) infection: case report and the review of literature.

BACKGROUND: To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). CASE: We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. CONCLUSIONS: Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.

AQP4-MOG Double-Positive Neuromyelitis Optica Spectrum Disorder: Case Report with Central and Peripheral Nervous System Involvement and Review of Literature.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.

Default-Mode Network Connectivity Changes Correlate with Attention Deficits in ALL Long-Term Survivors Treated with Radio- and/or Chemotherapy.

Whether chemotherapy (ChT) and radiotherapy (RT) determine neurocognitive impairment in acute lymphoblastic leukemia long-term survivors (ALL LTSs) through similar mechanisms affecting the same brain regions is still unknown. We compared neurocognitive alterations, regional brain tissue volumes (by voxel-based morphometry), and functional connectivity of the main default-mode network hubs (by seed-based analysis of resting state functional MRI data), in 13 ALL LTSs treated with RT and ChT (Group A) and 13 treated with ChT only (Group B). Group A performed significantly worse than Group B at the digit span and digit symbol tests (p = 0.023 and 0.013, respectively). Increased connectivity between the medial prefrontal cortex (the main anterior hub of the default-mode network) and the rolandic operculi was present in Group A compared to Group B, along with the absence of significant differences in regional brain tissue volumes. In these regions, the functional connectivity correlated inversely with the speed of processing scores, independent of treatment group. These results suggest that similar mechanisms may be involved in the neurocognitive deficits in ALL LTS patients, regardless of the treatment group. Further studies are needed to clarify whether these changes represent a direct expression of the mechanisms underlying the cognitive deficits or ineffective compensatory phenomena.

Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants.

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the 'molar tooth sign' and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

NO-HYPE: a novel hydrodynamic phantom for the evaluation of MRI flow measurements.

Accurate and reproducible measurement of blood flow profile is very important in many clinical investigations for diagnosing cardiovascular disorders. Given that many factors could affect human circulation, and several parameters must be set to properly evaluate blood flows with phase-contrast techniques, we developed an MRI-compatible hydrodynamic phantom to simulate different physiological blood flows. The phantom included a programmable hydraulic pump connected to a series of pipes immersed in a solution mimicking human soft tissues, with a blood-mimicking fluid flowing in the pipes. The pump is able to shape and control the flow by driving a piston through a dedicated software. Periodic waveforms are used as input to the pump to move the fluid into the pipes, with synchronization of the MRI sequences to the flow waveforms. A dedicated software is used to extract and analyze flow data from magnitude and phase images. The match between the nominal and the measured flows was assessed, and the scope of phantom variables useful for a reliable calibration of an MRI system was accordingly defined. Results showed that the NO-HYPE phantom is a valuable tool for the assessment of MRI scanners and sequence design for the MR evaluation of blood flows. Overview of the NOvel HYdrodynamic Phantom for the Evaluation of MRI flow measurements (NO-HYPE). Left: internal of the CompuFlow 1000 MR pump unit. Right: Setting of the NO-HYPE before a MRI acquisition session. Soft tissue mimicking material is hosted in the central part of the phantom (light blue chamber). Glass pipes pass through the chamber carrying the blood mimicking fluid.

Diffuse functional brain disconnection syndrome in critically ill patients with COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely related to severe respiratory syndrome; however, recent reports showed that it is capable of causing neurological disease. Here we report a case-series of 4 critically ill COVID-19 patients who recovered from pneumonia but showed serious neurological symptoms and eventually died.

Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) can rarely occur in Multiple Sclerosis (MS) patients undergoing dimethyl fumarate (DMF) treatment. Our case stresses the limits of current diagnostic and stratification risk criteria, highlighting the potential role of Magnetic Resonance Imaging (MRI) in advising clinical choices. CASE PRESENTATION: A 54 years old MS male patient treated with DMF, after 3 years of clinical stability developed a subacute clinical worsening. He had no severe lymphopenia but MRI signs suggestive of a coexistence of PML and MS activity. Although his viral title was negative, DMF was discontinued, with clinical and radiological improvement. CONCLUSIONS: This case highlights the challenges behind PML diagnosis, especially in patients not fulfilling the risk stratification criteria and that might present with concurrent disease activity, stressing the potential role of MRI in informing therapeutic decisions.

Brain Plasticity in Charcot-Marie-Tooth Type 1A Patients? A Combined Structural and Diffusion MRI Study.

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aim of our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 ± 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = -0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

A Prototype Microwave System for 3D Brain Stroke Imaging.

This work focuses on brain stroke imaging via microwave technology. In particular, the open issue of monitoring patients after stroke onset is addressed here in order to provide clinicians with a tool to control the effectiveness of administered therapies during the follow-up period. In this paper, a novel prototype is presented and characterized. The device is based on a low-complexity architecture which makes use of a minimum number of properly positioned and designed antennas placed on a helmet. It exploits a differential imaging approach and provides 3D images of the stroke. Preliminary experiments involving a 3D phantom filled with brain tissue-mimicking liquid confirm the potential of the technology in imaging a spherical target mimicking a stroke of a radius equal to 1.25 cm.

Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study.

PURPOSE: Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. METHODS: In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. RESULTS: GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. CONCLUSIONS: The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.

2D linear measures of ventricular enlargement may be relevant markers of brain atrophy and long-term disability progression in multiple sclerosis.

OBJECTIVES: Aim of this study was to investigate the reliability and validity of 2D linear measures of ventricular enlargement as indirect markers of brain atrophy and possible predictors of clinical disability. METHODS: In this retrospective longitudinal analysis of relapsing-remitting MS patients, brain volumes were computed at baseline and after 2 years. Frontal horn width (FHW), intercaudate distance (ICD), third ventricle width (TVW), and 4th ventricle width were obtained. Two-dimensional measures associated with brain volume at correlation analyses were entered in linear and logistic regression models testing the relationship with baseline clinical disability and 10-year confirmed disability progression (CDP), respectively. Possible cutoff values for clinically relevant atrophy were estimated via receiver operating characteristic (ROC) analyses and probed as 10-year CDP predictors using hierarchical logistic regression. RESULTS: Eighty-seven patients were available (61/26 = F/M; 34.1 ± 8.5 years). Moderate negative correlations emerged between ICD and TVW and normalized brain volume (NBV; p < 0.001) and percentage brain volume change per year (PBVC/y) and FHW, ICD, and TVW annual changes (p ≤ 0.005). Baseline disability was moderately associated with NBV, ICD, and TVW (p < 0.001), while PBVC/y predicted 10-year CDP (p = 0.01). A cutoff percentage ICD change per year (PICDC/y) value of 4.38%, corresponding to - 0.91% PBVC/y, correlated with 10-year CDP (p = 0.04). These estimated cutoff values provided extra value for predicting 10-year CDP (PBVC/y: p = 0.001; PICDC/y: p = 0.03). CONCLUSIONS: Two-dimensional measures of ventricular enlargement are reproducible and clinically relevant markers of brain atrophy, with ICD and its increase over time showing the best association with clinical disability. Specifically, a cutoff PICDC/y value of 4.38% could serve as a potential surrogate marker of long-term disability progression. KEY POINTS: • Assessment of ventricular enlargement as a rapidly accessible indirect marker of brain atrophy may prove useful in cases in which brain volume quantification is not practicable. • Two-dimensional linear measures of ventricular enlargement represent reliable, valid, and clinically relevant markers of brain atrophy. • A cutoff annualized percentage brain volume change of - 0.91% and the corresponding annualized percentage increase of 4.38% for intercaudate distance are able to discriminate patients who will develop long-term disability progression.

Solitary Cerebral Metastases vs. High-grade Gliomas: Usefulness of Two MRI Signs in the Differential Diagnosis.

BACKGROUND/AIM: The differentiation between cerebral metastases (CM) and high-grade gliomas (HGG) can be difficult on magnetic resonance imaging (MRI). The aim of this study was to evaluate the usefulness of searching two MRI signs (signal alteration in the adjacent cortex, SAAC, and peripheral rim sign, PRS), in order to distinguish between these entities. PATIENTS AND METHODS: A total of 61 patients were retrospectively enrolled (28 HGG, 33 CM). Fluid Attenuated Inversion Recovery (FLAIR) sequences were used to assess SAAC and contrast-enhanced T1-weighted sequences for PRS. RESULTS: A positive SAAC sign was present in 61% of HGG, and 12% of CM. Conversely, in SAAC-negative lesions, PRS was observed in 78% of CM and in 32% of HGG. Their association had a higher frequency in HGG than in the CM group (21 vs. 3%). CONCLUSION: While SAAC is specific for HGG and PRS, in the absence of SAAC, is relatively specific for CMs, their combined presence is highly suggestive of HGG.

Primary familial brain calcification caused by a novel homozygous MYORG mutation in a consanguineous Italian family.

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient's father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.

MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in Multiple Sclerosis.

PURPOSE: Different studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing-remitting multiple sclerosis (RR-MS) patients. METHODS: In this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6 years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps. RESULTS: Patients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome. CONCLUSIONS: MS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.

Reduced Intracranial Volume in Fabry Disease: Evidence of Abnormal Neurodevelopment?

Introduction: Lysosomal storage disorders (LSD) are often characterized by abnormal brain development, reflected by a reduction of intracranial volume (ICV). The aim of our study was to perform a volumetric analysis of intracranial tissues in Fabry Disease (FD), investigating possible reductions of ICV as a potential expression of abnormal brain development in this condition. Materials and Methods: Forty-two FD patients (15 males, mean age 43.3 ± 13.0 years) were enrolled along with 38 healthy controls (HC) of comparable age and sex. Volumetric MRI data were segmented using SPM12 to obtain intracranial tissue volumes, from which ICV values were derived. Results: Mean ICV of FD patients was 8.1% smaller compared to the control group (p < 5·10-5). Unlike what typically happens in neurodegenerative disorders, no significant differences emerged when comparing between the two groups the fractional volumes of gray matter, white matter and CSF (i.e., normalized by ICV), consistent with a harmonious volumetric reduction of intracranial structures. Discussion: The present results suggest that in FD patients an abnormality of brain development is present, expanding the current knowledge about central nervous system involvement in FD, further emphasizing the importance of an early diagnosis.

Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family.

BACKGROUND: Multiple Sclerosis (MS) is considered among possible differential diagnosis of Fabry Disease (FD), especially in early stages when findings are suggestive but not diagnostic for MS. We report the case of a family in which FD and MS coexist, offering an overview on clues for differential diagnosis and speculating on shared etiopathogenic mechanisms for these conditions. METHODS: Taking as starting point the diagnosis of FD in a dialysis patient during a screening programme, we retrospectively rebuilt his family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS. RESULTS: After genetic testing, two subjects were found positive to a new α-galactosidase A mutation, probably causative for FD classical variant. The two subjects meeting diagnostic criteria for MS were found negative to any GLA gene mutation, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with neither clinical nor instrumental evidence of FD and MS. CONCLUSIONS: Differential diagnosis between FD and MS may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct MRI interpretation may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to FD and MS.