Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Superficial siderosis in long-standing pilocytic astrocytoma.

BACKGROUND: Pilocytic astrocytoma (PA) rarely spreads along neuraxis, and association with superficial siderosis (SS) and chronic signs of intracranial hypertension is exceptional. CASE REPORT: A 48-year-old woman presented with slow onset hearing loss in the past year. Clinical examination revealed dysarthria, positive Romberg test, and severe optic neuropathy. Cerebrospinal fluid (CSF) analysis showed numerous red blood cells, increased proteins and LDH, and high opening pressure. Brain and spine MRI demonstrated extensive superficial siderosis, bone remodeling of the skull base and spine, and diffuse nodular leptomeningeal enhancement. Histological examination of a nodule in the dorsal spine evidenced PA. CONCLUSION: We report a case of PA associated with dural remodeling and SS. The mechanism of SS is unclear but might be related to meningeal tumor infiltration and altered CSF composition and resorption.

Adults with tetralogy of Fallot show specific features of cerebral small vessel disease: the BACH San Donato study.

Life expectancy in adults with congenital heart disease (ACHD) has increased. As these patients grow older, they experience aging-related diseases more than their healthy peers. To better characterize this field, we launched the multi-disciplinary BACH (Brain Aging in Congenital Heart disease) San Donato study, that aimed at investigating signs of brain injury in ACHD. Twenty-three adults with repaired tetralogy of Fallot and 23 age- and sex-matched healthy controls were prospectively recruited and underwent brain magnetic resonance imaging. White matter hyperintensities (WMHs) were segmented using a machine-learning approach and automatically split into periventricular and deep. Cerebral microbleeds were manually counted. A subset of 14 patients were also assessed with an extensive neuropsychological battery. Age was 41.78 ± 10.33 years (mean ± standard deviation) for patients and 41.48 ± 10.28 years for controls (p = 0.921). Albeit not significantly, total brain (p = 0.282) and brain tissue volumes (p = 0.539 for cerebrospinal fluid, p = 0.661 for grey matter, p = 0.793 for white matter) were lower in ACHD, while total volume (p = 0.283) and sub-classes of WMHs (p = 0.386 for periventricular WMHs and p = 0.138 for deep WMHs) were higher in ACHD than in controls. Deep WMHs were associated with poorer performance at the frontal assessment battery (r = -0.650, p = 0.012). Also, patients had a much larger number of microbleeds than controls (median and interquartile range 5 [3-11] and 0 [0-0] respectively; p < 0.001). In this study, adults with tetralogy of Fallot showed specific signs of brain injury, with some clinical implications. Eventually, accurate characterization of brain health using neuroimaging and neuropsychological data would aid in the identification of ACHD patients at risk of cognitive deterioration.

Neuromotor control associates with muscle weakness observed with McArdle sign of multiple sclerosis.

OBJECTIVE: Multiple Sclerosis (MS) is often accompanied by myelopathy, which may be associated with progressive worsening. A specific finding of MS-associated myelopathy is McArdle sign, wherein neck flexion is associated with prominent increased limb weakness relative to that detected with neck extension. In this study, we characterized neuromotor control properties of finger extensors in association with the McArdle sign. METHODS: A custom-built device was utilized to monitor torque production of the wrist extensors with simultaneous recording of surface electromyography of the extensor digitorum. The electromyography was decomposed and analyzed via both linear and nominal regressions. RESULTS: Linear regressions demonstrated a strong difference between groups for MS from healthy controls and other myelopathies for motor unit action potential amplitude and average firing rate (p < 0.001). Further, linear regression demonstrated good correlations of neuromotor variables to mechanical torque output (0.24 ≤ R2 ≤ 0.76). Nominal regression distinguished MS from healthy controls with an AUC of 0.87, specificity of 0.97, and sensitivity of 0.64. Nominal regression of MS from other myelopathies demonstrated an AUC of 0.88, specificity of 0.85, and sensitivity of 0.79. INTERPRETATION: These data demonstrate the neuromotor control factors that largely determine muscle force production change with the observation of McArdle sign; these neuromotor control factors can differentiate MS from both healthy controls and other myelopathy conditions.

MRI versus CT in the detection of brain lesions in patients with infective endocarditis before or after cardiac surgery.

PURPOSE: Imaging of brain involvement in infective endocarditis can drive the clinical management of this serious condition. MRI is very sensitive, but CT is more readily available. In this retrospective study, we compared the detection rates of CT and MRI. METHODS: After Ethics Committee approval, we retrospectively reviewed a series of 20 patients (13 males, median age 64 years) who underwent both CT and MRI either before or after cardiac surgery for definite infective endocarditis. Plain CT and MRI were evaluated for acute ischemic lesions, both punctuate and large, intraparenchymal hemorrhages, cerebral microbleeds, subarachnoid hemorrhages, abscesses, microabscesses, and meningitis. Qualitative assessment and McNemar test were performed. The value of contrast-enhanced scans (MRI, n = 14; CT, n = 9) and cognitive status were also assessed. RESULTS: A total of 166 lesions were identified on either technique: 137 (83%) on MRI only, 4 (2%) on CT only, and 25 (15%) on both techniques (p < 0.001). For these last 25 lesions, concordance on lesion type was only 16/25 (64%). MRI detected more microbleeds and ischemic lesions, while the 4 CT-only findings were false positives. Contrast-enhanced scans identified 68 enhancing lesions, mainly abscesses and microabscesses, and allowed a better characterization for 61/117 lesions (52%) with MRI, and for 11/81 (14%) with CT. Follow-up identified mild cognitive impairment in 6/13 and dementia in 3/13 patients. CONCLUSION: While CT rapidly excludes large hemorrhages in patients with infective endocarditis, MRI accurately distinguishes the whole spectrum of brain lesions, including small ischemic lesions, microbleeds, and microabscesses.

Biomechanical muscle stiffness measures of extensor digitorum explain potential mechanism of McArdle sign.

BACKGROUND: McArdle sign is a phenomenon of impaired gait and muscle weakness that occurs with neck flexion, immediately reversible with neck extension. A recent report measured the specificity of this sign for multiple sclerosis by measuring differences in peak torque of the extensor digitorum between neck extension and flexion. METHODS: This substudy included 73 participants (29 multiple sclerosis, 20 non-multiple sclerosis myelopathies, 5 peripheral nerve disorders, and 19 healthy controls). The effect of neck position was assessed on muscle stiffness and neuromechanical error of the extensor digitorum. FINDINGS: Patients with multiple sclerosis had greater neuromechanical error (sum of squared error of prediction) compared to controls (P = 0.023) and non-multiple sclerosis myelopathies (P = 0.003). Neuromechanical error also provided improved sensitivity/specificity of McArdle sign. Peak torque, muscle stiffness, and neuromechanical error could distinguish multiple sclerosis from other myelopathies with 80% specificity and 97% sensitivity (AUC = 0.95). INTERPRETATION: A decrease in muscle stiffness and neuromechanical error in neck flexion compared to extension are additional indicators for a diagnosis of multiple sclerosis. Analysis of muscle stiffness may provide insights into the pathophysiology of this specific clinical sign for multiple sclerosis. Furthermore, muscle stiffness may provide an additional accurate, simple assessment to evaluate multiple sclerosis therapeutic interventions and disease progression.

White Matter Hyperintensities Quantification in Healthy Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Although white matter hyperintensities (WMH) volumetric assessment is now customary in research studies, inconsistent WMH measures among homogenous populations may prevent the clinical usability of this biomarker. PURPOSE: To determine whether a point estimate and reference standard for WMH volume in the healthy aging population could be determined. STUDY TYPE: Systematic review and meta-analysis. POPULATION: In all, 9716 adult subjects from 38 studies reporting WMH volume were retrieved following a systematic search on EMBASE. FIELD STRENGTH/SEQUENCE: 1.0T, 1.5T, or 3.0T/fluid-attenuated inversion recovery (FLAIR) and/or proton density/T2 -weighted fast spin echo sequences or gradient echo T1 -weighted sequences. ASSESSMENT: After a literature search, sample size, demographics, magnetic field strength, MRI sequences, level of automation in WMH assessment, study population, and WMH volume were extracted. STATISTICAL TESTS: The pooled WMH volume with 95% confidence interval (CI) was calculated using the random-effect model. The I2 statistic was calculated as a measure of heterogeneity across studies. Meta-regression analysis of WMH volume on age was performed. RESULTS: Of the 38 studies analyzed, 17 reported WMH volume as the mean and standard deviation (SD) and were included in the meta-analysis. Mean and SD of age was 66.11 ± 10.92 years (percentage of men 50.45% ± 21.48%). Heterogeneity was very high (I2  = 99%). The pooled WMH volume was 4.70 cm3 (95% CI: 3.88-5.53 cm3 ). At meta-regression analysis, WMH volume was positively associated with subjects' age (ß = 0.358 cm3 per year, P < 0.05, R2  = 0.27). DATA CONCLUSION: The lack of standardization in the definition of WMH together with the high technical variability in assessment may explain a large component of the observed heterogeneity. Currently, volumes of WMH in healthy subjects are not comparable between studies and an estimate and reference interval could not be determined. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Functional brain connectivity abnormalities and cognitive deficits in neuromyelitis optica spectrum disorder.

BACKGROUND: Functional magnetic resonance imaging (fMRI) correlates of cognitive deficits have not been thoroughly studied in patients with neuromyelitis optica spectrum disorders (NMOSDs). OBJECTIVE: To investigate resting state (RS) functional connectivity (FC) abnormalities within the main cognitive networks in NMOSD patients and their correlation with cognitive performance. METHODS: We acquired RS fMRI from 25 NMOSD patients and 30 healthy controls (HC). Patients underwent an extensive neuropsychological evaluation. Between-group RS FC comparisons and correlations with cognitive performance were assessed on the main cognitive RS networks identified by independent component analysis. RESULTS: NMOSD patients showed higher RS FC versus HC in the precuneus of the default mode network (DMN) and right working memory network (WMN), as well as in several frontoparietal regions of the salience network (SN) and bilateral WMNs. Reduced frontal RS FC in NMOSD versus HC was detected in the left WMN. Increased RS FC in the DMN and right WMN was correlated with better cognitive performance, while decreased RS FC in the left WMN was associated with worse cognitive performance. CONCLUSION: Cognitive-network reorganization occurs in NMOSD. Clinico-imaging correlations suggest an adaptive role of increased RS FC. Conversely, reduced RS FC seems to be a maladaptive mechanism associated with a worse cognitive performance.

McArdle Sign: A Specific Sign of Multiple Sclerosis.

OBJECTIVE: To measure McArdle sign (rapidly reversible weakness induced by neck flexion) both qualitatively and quantitatively and to evaluate its specificity and clinical utility for diagnosis of multiple sclerosis (MS). PATIENTS AND METHODS: In this prospective study, McArdle sign was evaluated by a technician blinded to diagnosis by measuring changes in finger extensor strength in successive trials of neck extension and flexion, first clinically and then with a torque measurement device. We studied 25 healthy controls and 81 patients with finger extensor weakness. Patients were not selected for having McArdle sign. Fifty-two patients had MS, 24 had other myelopathies, and 5 had peripheral nerve lesions accounting for their weakness. The study was conducted between February 1, 2016, and June 30, 2017. RESULTS: The median clinical McArdle sign and the 2 quantitative measures of neck flexion-induced strength reduction were greater in patients with MS than in the other groups (P<.001). Baseline strength did not confound the difference. The area under the receiver operating characteristic curve was 0.84 (95% CI, 0.75-0.93) comparing patients with MS vs healthy controls and 0.84 (95% CI, 0.75-0.93) comparing MS vs patients with other myelopathies. The 2 quantitative and 1 clinical measurement of McArdle sign by the technician who performed the quantitative testing were correlated (r=.57 and r=.58; P<.001), and in turn, the technician's and unblinded referring physician's clinical assessments were correlated (r=.58; P<.001). McArdle sign was evident in some patients who had minor disability and who were in early phases of MS. CONCLUSION: McArdle sign, when defined as greater than 10% neck flexion-induced reduction in strength, is entirely specific and 65% sensitive for a diagnosis of MS when compared with other conditions that mimic MS-associated myelopathy. It may facilitate diagnosis in certain clinical situations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03122873.

Cross-modal plasticity among sensory networks in neuromyelitis optica spectrum disorders.

OBJECTIVE: To explore resting-state (RS) functional connectivity (FC) of the main sensory/motor networks of patients with neuromyelitis optica spectrum disorders (NMOSDs), clinically isolated optic neuritis (ON), and myelitis. METHODS: Clinical evaluation and RS fMRI were obtained from 28 NMOSD, 11 recurrent ON, and 12 recurrent myelitis patients and 30 healthy controls. Between-group RS FC comparisons and correlations with motor performance were assessed (SPM12) on the main sensory/motor RS networks (RSNs) identified by independent component analysis. Functional network connectivity analysis estimated inter-network connectivity. RESULTS: Intra- and inter-network RS FCs were reduced in RSNs associated to somatosensory modalities affected by pathology: regions of the primary visual network in ON patients, of the sensorimotor networks in myelitis patients, and of the sensorimotor and secondary visual networks in NMOSD patients. The opposite trend was observed in regions of RSNs spared by pathology: the auditory and part of visual networks in NMOSD, the secondary visual and sensorimotor networks in ON, and the primary visual network in myelitis patients. Better motor performance correlated with higher RS FC of spared RSNs. CONCLUSION: Sensory and motor RSN abnormalities occur in NMOSD. Loss of function within disease-target networks may elicit cross-modal plasticity across sensory networks potentially preserving clinical function.

A cancer-mimicking diagnosis of peritoneal carcinosis: report of a case of abdominal non-tuberculous mycobacterial infection.

Abdominal non-tuberculous mycobacterial infection is a rare condition in healthy patients. When it occurs, it leads to the appearance of typical findings of peritoneal involvement, such as thickening of the peritoneal leaflets and the omentum, ascites and enlargement of lymph nodes and of mesenteric nodules. These findings may be misdiagnosed as tumour peritoneal implants. In case of spontaneous regression of the peritoneal involvement and ascites, as well as in the absence of malignancy, the suspicion of infectious disease, including abdominal nontuberculous mycobacterial infection, should be considered.

Elsberg syndrome: A rarely recognized cause of cauda equina syndrome and lower thoracic myelitis.

OBJECTIVE: Elsberg syndrome (ES) is an established but often unrecognized cause of acute lumbosacral radiculitis with myelitis related to recent herpes virus infection. We defined ES, determined its frequency in patients with cauda equina syndrome (CES) with myelitis, and evaluated its clinical, radiologic, and microbiologic features and outcomes. METHODS: We searched the Mayo Clinic medical records for ES and subsequently for combinations of index terms to identify patients with suspected CES and myelitis. RESULTS: Our search yielded 30 patients, 2 diagnosed with ES and an additional 28 with clinical or radiologic evidence of CES retrospectively suspected of having ES. We classified patients in 5 groups according to diagnostic certainty. MRI and EMG confirmed that 2 had only myelitis, 5 only radiculitis, and 16 both. Two had preceding sacral herpes infection and 1 oral herpes simplex. Spinal cord lesions were commonly multiple, discontinuous, not expansile, and centrally or ventrally positioned. Lesions generally spared the distal conus. Nerve root enhancement was occasionally prominent and was smooth rather than nodular. Lymphocytic CSF pleocytosis was common. Thirteen patients (43%) had viral isolation studies, which were commonly delayed; the delay may have accounted for the low rate of viral detection. Acyclovir was administered to 6 patients. Most patients recovered with sequelae; 1 patient experienced encephalomyelitis and died. CONCLUSION: ES is a definable condition likely responsible for 10% of patients with combined CES and myelitis. Radiologic findings are not entirely specific but may help in differentiating ES from some competing diagnostic considerations. We propose criteria to facilitate diagnosis.