Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

Neuromuscular imaging in clinical practice: an ESNR survey of 30 centers.

PURPOSE: We assessed the current clinical imaging practice in the primary evaluation of neuromuscular disorders (NMD), with respect to standardized imaging, evaluation and reporting through a European and extra-European-wide survey. METHODS: An online questionnaire was emailed to all European Society of Neuroradiology (ESNR) members (n = 1662) who had expressed their interest in NMD. The questionnaire featured 40 individual items. Information was gathered on the context of the practices, available and preferred imaging modalities, applied imaging protocols and standards for interpretation, reporting and communication. RESULTS: A total of 30 unique entries from European and extra-European academic and non-academic institutions were received. Of these, 70% were neuroradiologists, 23% general radiologists and 7% musculoskeletal radiologists. Of the 30 responding institutes, 40% performed from 20 to 50 neuromuscular scans per year for suspected NMD. The principal modality used for a suspected myopathy was magnetic resonance imaging (MRI) (50%) or "mainly MRI" (47%). The primary imaging modality used for the evaluation of patients suspected of a neuropathy was MRI in 63% of all institutions and "mainly MRI" in 37%. For both muscle and nerve pathology, pelvic girdle and inferior limbs are the most scanned parts of the body (28%), followed by the thigh and leg (24%), whole body MR (24%), scapular girdle (16%), and the thigh in just 8% of institutions. Multiplanar acquisitions were performed in 50% of institutions. Convectional sequences used for muscle MRI included T2-STIR (88%), 2D T1weighted (w) (68%), T1 Dixon or equivalent (52%), T2 Dixon (40%), DWI (36%), 2D T2w (28%), T1 3D and T2 3D (20% respectively). For nerve MRI conventional sequences included T2-STIR (80%), DWI (56%), T2 3D (48%), 2D T2w (48%), T1 3D (44%), T1 Dixon or equivalent (44%), 2D T1 (36%), T2 Dixon (28%). Quantitative sequences were used regularly by 40% respondents. While only 28% of institutions utilized structured reports, a notable 88% of respondents expressed a desire for a standardized consensus structured report. Most of the respondents (93%) would be interested in a common MRI neuromuscular protocol and would like to be trained (87%) by the ESNR society with specific neuromuscular sessions in European annual meetings. CONCLUSIONS: Based on the survey findings, we can conclude that the current approach to neuromuscular imaging varies considerably among European and extra-European countries, both in terms of image acquisition and post-processing. Some of the challenges identified include the translation of research achievements (related to advanced imaging) into practical applications in a clinical setting, implementation of quantitative imaging post-processing techniques, adoption of structured reporting methods, and communication with referring physicians.

Intracranial Pressure Thresholds for Cerebral Autoregulation Impairment: Age-Stratified Analysis of Ultra-Low-Frequency Pressure Reactivity Index (UL-PRx) in Traumatic Brain Injury.

BACKGROUND: The study investigated the effectiveness of low-frequency sampling in detecting alterations in cerebrovascular reactivity (CVR) associated with changes in intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across different age groups. The primary objective was to investigate an ICP threshold that indicates a decrease in CVR as evidenced by a significant increase in the ultra-low-frequency pressure reactivity index (UL-PRx). Additionally, the study aimed to develop an age-based categorization method for patients with TBI to investigate the differences between these ICP thresholds in different age groups. METHODS: In this retrospective analysis, data from 263 patients with TBI were prospectively collected. ICP and mean arterial pressure were extracted from the hospital database at 5-min intervals. Demographic details, clinical presentation, computed tomography scans, neurosurgical interventions, and 12-months outcome were recorded. ICP versus UL-PRx values were categorized into ICP bins and graphically represented with boxplots for each age group, illustrating how as ICP values rise, there is a bin (age-tailored ICP [AT-ICP]) beyond which UL-PRx shows a sudden increase, indicating CVR loss. Homogeneous age groups were established to obtain a consistent AT-ICP threshold. The discriminatory ability of the AT-ICP thresholds was compared with the guideline-recommended thresholds by calculating the area under the Receiver Operating Characteristic curve of the ICP-derived indices (dose above threshold, and the hourly dosage above threshold). RESULTS: Age groups 0-5, 6-20, 21-60, 61-70, and 71-85 years were the best age subdivisions, corresponding to AT-ICP thresholds of 20, 30, 35, 25, and 30 mmHg, respectively. The AT-ICP thresholds exhibited better discriminative ability compared with the guideline-recommended thresholds. CONCLUSIONS: The AT-ICP thresholds offer a novel approach for estimating CVR impairment and the developed method represents an alternative solution to address the age stratification issue in patients with TBI.

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML. METHODS: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides. RESULTS: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up. INTERPRETATION: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779.

Neuroimaging in patients with COVID-19: a neuroradiology expert group consensus.

Neurological and neuroradiological manifestations in patients with COVID-19 have been extensively reported. Available imaging data are, however, very heterogeneous. Hence, there is a growing need to standardise clinical indications for neuroimaging, MRI acquisition protocols, and necessity of follow-up examinations. A NeuroCovid working group with experts in the field of neuroimaging in COVID-19 has been constituted under the aegis of the Subspecialty Committee on Diagnostic Neuroradiology of the European Society of Neuroradiology (ESNR). The initial objectives of this NeuroCovid working group are to address the standardisation of the imaging in patients with neurological manifestations of COVID-19 and to give advice based on expert opinion with the aim of improving the quality of patient care and ensure high quality of any future clinical studies. KEY POINTS: • In patients with COVID-19 and neurological manifestations, neuroimaging should be performed in order to detect underlying causal pathology. • The basic MRI recommended protocol includes T2-weighted, FLAIR (preferably 3D), and diffusion-weighted images, as well as haemorrhage-sensitive sequence (preferably SWI), and at least for the initial investigation pre and post-contrast T1 weighted-images. • 3D FLAIR should be acquired after gadolinium administration in order to optimise the detection of leptomeningeal contrast enhancement.

Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene.

Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.

The risk of infection in patients with multiple sclerosis treated with disease-modifying therapies: A Delphi consensus statement.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Vaccinations in patients with multiple sclerosis: A Delphi consensus statement.

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of infection. Vaccination can mitigate these risks but only if safe and effective in MS patients, including those taking disease-modifying drugs. METHODS: A modified Delphi consensus process (October 2017-June 2018) was used to develop clinically relevant recommendations for making decisions about vaccinations in patients with MS. A series of statements and recommendations regarding the efficacy, safety and timing of vaccine administration in patients with MS were generated in April 2018 by a panel of experts based on a review of the published literature performed in October 2017. RESULTS: Recommendations include the need for an 'infectious diseases card' of each patient's infectious and immunisation history at diagnosis in order to exclude and eventually treat latent infections. We suggest the implementation of the locally recommended vaccinations, if possible at MS diagnosis, otherwise with vaccination timing tailored to the planned/current MS treatment, and yearly administration of the seasonal influenza vaccine regardless of the treatment received. CONCLUSION: Patients with MS should be vaccinated with careful consideration of risks and benefits. However, there is an urgent need for more research into vaccinations in patients with MS to guide evidence-based decision making.

Should frequent MRI monitoring be performed in natalizumab-treated MS patients? A contribution to a recent debate.

BACKGROUND: Brain magnetic resonance imaging (MRI) is the most effective surveillance tool for the detection of asymptomatic progressive multifocal leukoencephalopathy (PML). However, the optimal frequency for routine MRI surveillance is under-investigated. OBJECTIVE: To understand whether, upon their first MRI appearance, PML lesions present a difference in volume when comparing patients who frequently underwent MRI surveillance (3/4 months) with those who were assessed at longer intervals (6/12 months) and to understand the impact of the volume of lesions on clinical outcome. METHODS: The data of patients included in the Italian PML cohort were retrospectively analysed. Patients who had all the pre-diagnostic MRI scans available (n = 37) were included. The volume of PML lesion was calculated by manually outlining the PML lesion. RESULTS: Compared with patients who underwent MRI examination at least every 4 months, patients who were assessed less frequently had a lesion of significantly higher volume (median: 2567 (883-3583) vs. 664 mm3 (392-963) p = 0.006) and suffered a higher rate of disability (median: 2.25 expanded disability status scale points (-2.5 to 8) vs. 0.5 (-1 to 2.5) p = 0.004). CONCLUSION: The positive clinical outcome of patients undergoing frequent MRI surveillance and the small volume of the PML lesion upon first appearance justify a frequent surveillance using MRI in patients at high risk of PML.

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.

Brain microvascular occlusive disorder in COVID-19: a case report.

We describe the case of a COVID-19 patient with severely impaired consciousness after sedation hold, showing magnetic resonance imaging (MRI) findings of (i) acute bilateral supratentorial ischemic lesions involving the fronto-parietal white matter and the corpus callosum and (ii) multiple diffuse susceptibility weighted imaging (SWI) hypointense foci, infra and supratentorial, predominantly bithalamic, suggestive of microhemorrhage or alternatively microthrombi. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA was detected in the cerebrospinal fluid. Our findings suggest the occurrence of vascular damage, predominantly involving microvessels. The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications, are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain.

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution.

OBJECTIVE: Early diagnosis of natalizumab-related progressive multifocal leucoencephalopathy (NTZ-PML) in multiple sclerosis has been deemed a major priority by the regulatory agencies but has yet to become a reality. The current paper aims to: (1) investigate whether patients with NTZ-PML pass through a prolonged presymptomatic phase with MRI abnormalities, (2) estimate the longitudinal PML lesion volume increase during the presymptomatic phase and (3) estimate the presymptomatic phase length and its impact on therapy duration as a risk stratification parameter. METHODS: All Italian patients who developed NTZ-PML between 2009 and 2018 were included. The data of patients with available prediagnostic MRI were analysed (n=41). Detailed clinical and neuroradiological information was available for each participant. RESULTS: (1) PML lesions were detectable in the presymptomatic phase in 32/41 (78%) patients; (ii) the lesion volume increased by 62.8 % for each month spent in the prediagnostic phase; (3) the prediagnostic phase length was 150.8±74.9 days; (4) PML MRI features were detectable before the 24th month of therapy in 31.7 % of patients in our cohort. CONCLUSIONS: Considering the latency of PML clinical manifestation, the presymptomatic phase length supports the usefulness of MRI surveillance every 3-4 months. Early diagnosis could prompt a better outcome for patients due to the relationship between lesion volume and JC virus infection. The insight from this study might also have an impact on risk stratification algorithms, as therapy duration as a parameter of stratification appears to need reassessment.

Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy.

A 31-year-old woman affected by multiple sclerosis (MS) experienced generalized tonic-clonic seizures 2 months after the second alemtuzumab cycle. Positive JC virus (JCV)-DNA in cerebrospinal fluid (CSF) and lesion iconography at magnetic resonance imaging (MRI) were suggestive of progressive multifocal leukoencephalopathy (PML). After 1 month, during full-blown immune reconstitution inflammatory syndrome, JCV-DNA became negative and symptoms gradually improved. New T- and B-cell output and T- and B-cell diversity were low and lymphocytes poorly responded to stimulation. This is the first case of an alemtuzumab-treated patient with clinical symptoms and radiological features compatible with PML. The lack of large T- and B-cell diversity, necessary for JCV recognition, is likely to have concurred to PML insurgence.

Four cases of natalizumab-related PML: a less severe course in extended interval dosing?

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a severe adverse event of natalizumab (NTZ). The administration of NTZ with extended interval dosing (EID) has been proposed as a strategy to potentially reduce the incidence of PML while maintaining its therapeutic efficacy. METHODS: In the current paper, we describe 4 cases of NTZ-PML in EID included in the Italian PML cohort. RESULTS: The patients developed PML after at least 38 NTZ infusions. Their John Cunningham virus (JCv) index was > 1.5, and patients had not previously used immunosuppressant. Two patients were asymptomatic at PML onset, while two had mild motor impairment of the right hand and anomia, respectively. All of them had undetectable viral load but one (37 JCv copies/ml). In all patients, MRI revealed unilobar lesions with deferred contrast enhancement suggestive of immune reconstitution. The clinical course ended with a favorable clinical outcome (ΔEDSS up to 1). CONCLUSIONS: Although PML in EID seems to occur less frequently than in conventional dosing regimen, strict monitoring of high-risk patients contributed to the indolent course observed in the four described cases, characterized by a prolonged pre-symptomatic phase, paucisymptomatic onset, low JCv load, less severe functional impairment during immune reconstitution, and a mild disability burden.

Value of structured reporting in neuromuscular disorders.

OBJECTIVE: To assess whether structured reports (SRs) of MRI in patients with inherited neuromuscular disorders (IND) provide more clinically relevant information than non-structured reports (NSRs) and whether neuroradiologists' expertise affects completeness of reports. MATERIAL AND METHODS: Lower limbs' MRI reports of patients with IND produced by neuroradiologists with different level of expertise (> 15 years vs. < 15 years of experience in reading IND-MRI) before and after implementation of a SR template were included. Reports were assessed for the presence of 9 key features relevant for IND management. Reports and images were evaluated by neurologists who assessed: disease-specific muscular involvement pattern; presence of sufficient information to order the appropriate genetic/diagnostic tests; presence of sufficient information to make therapeutic decision/perform biopsy and necessity to review MRI images. Mann-Whitney and Fisher's exact tests were used to compare the number of key features for NSR and SR and neurologists' answers for reports produced by neuroradiologists with different experience. RESULTS: Thirty-one SRs and 101 NSRs were reviewed. A median of 8 and 6 key features was present in SR and NSR, respectively (p value < 0.0001). When reports were produced by less expert neuroradiologists, neurologists recognized muscular involvement pattern, had sufficient information for clinical decision-making/perform biopsy more often with SR than NSR (p values: < 0.0001), and needed to evaluate images less often with SR (p value: 0.0001). When reports produced by expert neuroradiologists were evaluated, no significant difference in neurologists' answers was observed. CONCLUSION: SR of IND-MRI contained more often clinically relevant information considered important for disease management than NSR. Radiologist's expertise affects completeness of NSR reports.

Diagnostic and Prognostic Value of JC Virus DNA in Plasma in Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (John Cunningham; JCV) that affects patients with impaired immune systems. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is uncertain. Methods: We retrospectively analyzed plasma samples from PML patients that were drawn close to disease onset and from controls without PML. In PML patients, we compared plasma JCV-DNA detection and levels to clinical and laboratory parameters, and patient survival. Results: JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, human immunodeficiency virus [HIV] negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive), respectively. Among 16 PML patients with undetectable CSF JCV-DNA, 4 (25%) had detectable plasma JCV-DNA. Plasma JCV-DNA levels were independently associated with CSF levels (P < .0001) and previous corticosteroid treatment (P = .012). Higher plasma JCV-DNA levels were associated with disease progression in HIV-negative patients (P = .005); in HIV-positive patients, there was an increased risk of progression only in those treated with combination antiretroviral therapy (cART; P < .0001). Conclusions: Testing JCV-DNA in plasma might complement PML diagnosis, especially when CSF is unavailable or JCV-DNA not detectable in CSF. In addition, JCV-DNA plasma levels could be useful as a marker of disease progression in both HIV-negative and cART-treated, HIV-positive PML patients.

To do or not to do? plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy.

OBJECTIVE: To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX+ , no = PLEX- ) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab-related progressive multifocal leukoencephalopathy (PML) and full-blown immune reconstitution inflammatory syndrome (PML-IRIS). METHODS: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: (1) a Cox model to investigate their impact on full-blown PML-IRIS latency; (2) an analysis of variance ANOVA to investigate their impact on IRIS duration; and (3) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of Expanded Disability Status Scale [EDSS]). RESULTS: Treatment with PLEX was not associated to PML-IRIS latency (hazard ratio [HR] = 1.05; p = 0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX+ and PLEX- patients; p = 0.028). Receiving proST versus therST was not associated to IRIS latency (HR = 0.67; p = 0.39) or duration (p = 0.95). Patients who underwent proST had a significantly higher EDSS increase during PML (0.09 EDSS points per month; p = 0.04) as compared to those who had therST. INTERPRETATION: This study highlights that: (1) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX and (2) caution on the early use of steroids is suggested because their prophylactic use to prevent full-blown PML-IRIS seems to negatively impact on the longitudinal disability course. Ann Neurol 2017;82:697-705.

Triggered intravoxel incoherent motion MRI for the assessment of calf muscle perfusion during isometric intermittent exercise.

The main aim of this paper was to propose triggered intravoxel incoherent motion (IVIM) imaging sequences for the evaluation of perfusion changes in calf muscles before, during and after isometric intermittent exercise. Twelve healthy volunteers were involved in the study. The subjects were asked to perform intermittent isometric plantar flexions inside the MRI bore. MRI of the calf muscles was performed on a 3.0 T scanner and diffusion-weighted (DW) images were obtained using eight different b values (0 to 500 s/mm2 ). Acquisitions were performed at rest, during exercise and in the subsequent recovery phase. A motion-triggered echo-planar imaging DW sequence was implemented to avoid movement artifacts. Image quality was evaluated using the average edge strength (AES) as a quantitative metric to assess the motion artifact effect. IVIM parameters (diffusion D, perfusion fraction f and pseudo-diffusion D*) were estimated using a segmented fitting approach and evaluated in gastrocnemius and soleus muscles. No differences were observed in quality of IVIM images between resting state and triggered exercise, whereas the non-triggered images acquired during exercise had a significantly lower value of AES (reduction of more than 20%). The isometric intermittent plantar-flexion exercise induced an increase of all IVIM parameters (D by 10%; f by 90%; D* by 124%; fD* by 260%), in agreement with the increased muscle perfusion occurring during exercise. Finally, IVIM parameters reverted to the resting values within 3 min during the recovery phase. In conclusion, the IVIM approach, if properly adapted using motion-triggered sequences, seems to be a promising method to investigate muscle perfusion during isometric exercise.

Thoracic Outlet Syndrome in the Overhead Athlete: A Report of 2 Cases of Subclavius Posticus Muscle.

Subclavius posticus muscle is a supernumerary anatomical variation of the subclavius muscle. The aim of this study was to show the possible contribution of the posticus muscle in the development of unilateral thoracic outlet syndrome (TOS) in overhead athletes, presenting hypertrophy of the dominant arm due to their sport activity. Reported here are 2 young overhead athletes complaining pain, paresthesia, weakness in the dominant upper limb, although presenting none of the main shoulder and neurological disorders. After developing subclavian vein thrombosis, TOS was suspected and finally diagnosed by dynamic magnetic resonance angiography, which also showed bilateral subclavius posticus muscle in both patients. Despite bilateral subclavius posticus, TOS was only evident in the dominant limb in which the association of hypertrophy of lateral cervical muscles, resulting from the overhead sport activity, to the subclavius posticus likely led to a significant reduction of the upper thoracic outlet space.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

OBJECTIVE: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity. METHODS: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio. RESULTS: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD. CONCLUSIONS: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.