Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.

Targeted magnetic resonance imaging (tMRI) of small changes in the T1 and spatial properties of normal or near normal appearing white and gray matter in disease of the brain using divided subtracted inversion recovery (dSIR) and divided reverse subtracted inversion recovery (drSIR) sequences.

This review describes targeted magnetic resonance imaging (tMRI) of small changes in the T1 and the spatial properties of normal or near normal appearing white or gray matter in disease of the brain. It employs divided subtracted inversion recovery (dSIR) and divided reverse subtracted inversion recovery (drSIR) sequences to increase the contrast produced by small changes in T1 by up to 15 times compared to conventional T1-weighted inversion recovery (IR) sequences such as magnetization prepared-rapid acquisition gradient echo (MP-RAGE). This increase in contrast can be used to reveal disease with only small changes in T1 in normal appearing white or gray matter that is not apparent on conventional MP-RAGE, T2-weighted spin echo (T2-wSE) and/or fluid attenuated inversion recovery (T2-FLAIR) images. The small changes in T1 or T2 in disease are insufficient to produce useful contrast with conventional sequences. To produce high contrast dSIR and drSIR sequences typically need to be targeted for the nulling TI of normal white or gray matter, as well as for the sign and size of the change in T1 in these tissues in disease. The dSIR sequence also shows high signal boundaries between white and gray matter. dSIR and drSIR are essentially T1 maps. There is a nearly linear relationship between signal and T1 in the middle domain (mD) of the two sequences which includes T1s between the nulling T1s of the two acquired IR sequences. The drSIR sequence is also very sensitive to reductions in T1 produced by Gadolinium based contrast agents (GBCAs), and when used with rigid body registration to align three-dimensional (3D) isotropic pre and post GBCA images may be of considerable value in showing subtle GBCA enhancement. In serial MRI studies performed at different times, the high signal boundaries generated by dSIR and drSIR sequences can be used with rigid body registration of 3D isotropic images to demonstrate contrast arising from small changes in T1 (without or with GBCA enhancement) as well as small changes in the spatial properties of normal tissues and lesions, such as their site, shape, size and surface. Applications of the sequences in cases of multiple sclerosis (MS) and methamphetamine dependency are illustrated. Using targeted narrow mD dSIR sequences, widespread abnormalities were seen in areas of normal appearing white matter shown with conventional T2-wSE and T2-FLAIR sequences. Understanding of the features of dSIR and drSIR images is facilitated by the use of their T1-bipolar filters; to explain their targeting, signal, contrast, boundaries, T1 mapping and GBCA enhancement. Targeted MRI (tMRI) using dSIR and drSIR sequences may substantially improve clinical MRI of the brain by providing unequivocal demonstration of abnormalities that are not seen with conventional sequences.

Prevalence of amyloid in ligamentum flavum of patients with lumbar spinal stenosis.

BACKGROUND: Transthyretin (ATTR) amyloidosis is often diagnosed in an advanced stage, when irreversible cardiac damage has occurred. Lumbar spinal stenosis (LSS) may precede cardiac ATTR amyloidosis by many years, offering the opportunity to detect ATTR already at the time of LSS surgery. We prospectively assessed the prevalence of ATTR in the ligamentum flavum by tissue biopsy in patients aged >50 years undergoing surgery for LSS. METHODS: Ligamentum flavum thickness was assessed pre-operatively on axial T2 magnetic resonance imaging (MRI) slices. Tissue samples from ligamentum flavum were screened centrally by Congo red staining and immunohistochemistry (IHC). RESULTS: Amyloid in the ligamentum flavum was detected in 74/94 patients (78.7%). IHC revealed ATTR in 61 (64.9%), whereas amyloid subtyping was inconclusive in 13 (13.8%). Mean thickness of ligamentum flavum was significantly higher at all levels in patients with amyloid (p < .05). Patients with amyloid deposits were older (73.1 ± 9.2 vs. 64.6 ± 10.1 years, p = .01). No differences in sex, comorbidities, previous surgery for carpal tunnel syndrome or LSS were observed. CONCLUSIONS: Amyloid, mostly of the ATTR subtype, was found in four out of five patients with LSS and is associated with age and ligamentum flavum thickness. Histopathological work-up of ligamentum flavum might inform future decision making.

Differentiating solitary brain metastases from high-grade gliomas with MR: comparing qualitative versus quantitative diagnostic strategies.

PURPOSE: To investigate the diagnostic efficacy of MRI diagnostic algorithms with an ascending automatization, in distinguishing between high-grade glioma (HGG) and solitary brain metastases (SBM). METHODS: 36 patients with histologically proven HGG (n = 18) or SBM (n = 18), matched by size and location were enrolled from a database containing 655 patients. Four different diagnostic algorithms were performed serially to mimic the clinical setting where a radiologist would typically seek out further findings to reach a decision: pure qualitative, analytic qualitative (based on standardized evaluation of tumor features), semi-quantitative (based on perfusion and diffusion cutoffs included in the literature) and a quantitative data-driven algorithm of the perfusion and diffusion parameters. The diagnostic yields of the four algorithms were tested with ROC analysis and Kendall coefficient of concordance. RESULTS: Qualitative algorithm yielded sensitivity of 72.2%, specificity of 78.8%, and AUC of 0.75. Analytic qualitative algorithm distinguished HGG from SBM with a sensitivity of 100%, specificity of 77.7%, and an AUC of 0.889. The semi-quantitative algorithm yielded sensitivity of 94.4%, specificity of 83.3%, and AUC = 0.889. The data-driven algorithm yielded sensitivity = 94.4%, specificity = 100%, and AUC = 0.948. The concordance analysis between the four algorithms and the histologic findings showed moderate concordance for the first algorithm, (k = 0.501, P < 0.01), good concordance for the second (k = 0.798, P < 0.01), and third (k = 0.783, P < 0.01), and excellent concordance for fourth (k = 0.901, p < 0.0001). CONCLUSION: When differentiating HGG from SBM, an analytical qualitative algorithm outperformed qualitative algorithm, and obtained similar results compared to the semi-quantitative approach. However, the use of data-driven quantitative algorithm yielded an excellent differentiation.

Magnetic resonance imaging of pilocytic astrocytomas in adults with histopathologic correlation: a report of six consecutive cases.

Pilocytic astrocytoma is a WHO grade I tumor usually diagnosed in pediatric patients, and rarely encountered in the adult population. Therefore, available information about the magnetic resonance imaging characteristics of adult pilocytic astrocytoma is scarce. We report on the MRI features and corresponding histopathologic findings of six consecutive aPA cases diagnosed. The tumors were encountered in both infra- and supratentorial compartments, and their MRI characteristics were quite heterogeneous. Features included the typical solid-cystic appearance located in the cerebellum as well as the relatively unusual multifocal and/or hemorrhagic features located intra-ventricularly. The aPA MRI characteristics are remarkably variable, and might mimic those of higher grade tumors in adult patients.

De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis.

BACKGROUND: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens. OBJECTIVE: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis. METHODS: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19+ B cell, and IgG concentrations were analyzed. RESULTS: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5-4.5) and 12 months (3.5 (2.5-5.5) p = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9-45.2) pg/mL) and 12 months (9.1 (5.9-21.3) pg/mL, p = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = -0.439, p = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71-22.9, p = 0.005). CONCLUSION: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

Multimodal assessment of motor pathways and intracortical connections in functional hemispherectomy.

PURPOSE: For selected children with medically intractable epilepsy, hemispherectomy can be an excellent treatment option and its efficacy in achieving seizure freedom or reduction in seizure frequency has been shown in several studies, but patients' selection could not be straightforward and often it is taken on subjective basis. We described a multimodal approach to assess patient eligible for hemispherectomy and possibly predicting post-surgical outcomes. METHODS: We describe pre- and post-surgical clinical features along with neuroradiological results by magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MR-tractography (MRT), and neurophysiological study by single and paired pulses transcranial magnetic stimulation (TMS) in a child with cerebral palsy with epileptic encephalopathy, eligible for epilepsy surgery. RESULTS: Presurgical TMS evaluation showed a lateralization of motor function on the left motor cortex for both arms, and results were confirmed by MRI studies. Interestingly, after surgery, both epilepsy and motor performances improved and TMS showed enhancement of intracortical inhibition and facilitation activity. CONCLUSION: Functional hemispherectomy is an effective treatment for drug-resistant epilepsy, and multimodal presurgical assessment may be a useful approach to guide surgeons in selecting patients. Moreover, pre- and post-surgical evaluation of these patients may enhance our understanding of brain plasticity phenomena.

Vertebral body stent augmentation to reconstruct the anterior column in neoplastic extreme osteolysis.

BACKGROUND: Extensive lytic lesions of the vertebral body (VB) increase risk of fracture and instability and require stabilization of the anterior column. Vertebral augmentation is an accepted treatment option, but when osteolysis has extensively destroyed the VB cortical boundaries (a condition herein defined as 'extreme osteolysis'), the risk of cement leakage and/or insufficient filling is high. Vertebral body stents (VBSs) might allow partial restoration of VB height, cement containment, and reinforcement, but their use in extreme osteolysis has not been investigated. OBJECTIVE: To assess retrospectively the feasibility and safety of VBS augmentation in patients with 'extreme osteolysis' of the VB. METHODS: We retrospectively analyzed 41 treated vertebrae (from T1 to L5). VB reconstruction was assessed on postprocedure CT images and rated on a qualitative 4-point scale (poor-fair-good-excellent). Clinical and radiological follow-up was performed at 1 month and thereafter at intervals in accordance with oncological protocols. RESULTS: VBS augmentation was performed at 12 lumbar and 29 thoracic levels, with bilateral VBS in 23/41. VB reconstruction was judged satisfactory (good or excellent) in 37/41 (90%) of levels. Bilateral VBS received higher scores than unilateral (p=0.057, Pearson's X2). We observed no periprocedural complications. Cement leaks (epidural or foraminal) occurred at 5/41 levels (12.2%) without clinical consequences. Follow-up data were available for 27/29 patients, extending beyond 6 months for 20 patients (7-28 months, mean 15.3 months). VBS implant stability was observed in 40/41 cases (97.5%). CONCLUSIONS: Our results support the use of VBS as a minimally invasive, safe and effective option for reconstructing the anterior column in prominent VB osteolysis.

Operator radiation doses during CT-guided spine procedures.

OBJECTIVES: To perform a pilot study to quantify the radiation dose incident on operators during CT-guided interventional spine procedures, and provide a quick method to approximate it based on the total amount of radiation reported by the CT scanner. PATIENTS AND METHODS: Data retrospectively obtained from 26 consecutive CT-guided spine procedures, encompassing a variety of interventions. Intermittent low-dose limited-coverage CT-scanning performed using a "step and shoot" mode to visualize needle advancement. The operator wore an electronic direct dosimeter to record the dose measured above the operator's lead apron [µGy] for each procedure. Total amount of radiation used for CT-guidance quantified by the Dose-Length Product (DLP) [mGy-cm] provided by the CT scanner. The relationship between the operator's dose and the DLP was assessed. RESULTS: Average and median operator's dose were 2.3 and 1.9 µGy, respectively, with half of these values ranging between 0.7 and 2.5 µGy. Average and median DLP values used to perform the CT-guided procedure were 58 and 54 mGy-cm respectively, and half of these values ranged between 38 and 68 mGy-cm. There was a statistically significant correlation between the operator's dose and the DLP used to perform CT-guidance (r = 0.61), with an operator's dose-DLP conversion factor of 0.04 µGy / 1 mGy-cm (range: 0.006-0.083 µGy / 1 mGy-cm). CONCLUSIONS: In our series, the average amount of radiation used during CT guided procedures was about 50 mGy-cm (DLP), and the corresponding average operator's dose was about 2 µGy. We showed how an approximate estimate of the operator's dose could be obtained right after each procedure, based on the CT-scanner DLP output.

Intradiploic encephalocele of the primary motor cortex in an adult patient: electrophysiological implications during surgery.

Encephaloceles are herniations of brain parenchyma through congenital or acquired osseous-dural defects of the skull base or cranial vault. Different types of symptoms, due to CSF fistulas, meningitis, or seizures, are often associated with this condition. The authors present a rare case of spontaneous right frontal parasagittal encephalocele in a 70-year-old man who was experiencing a spastic progressive paresis of his left lower limb. Results of routine electrophysiological workup (motor evoked potentials, somatosensory evoked potentials, and electroneuromyography), as well as those of MRI of the spinal cord, were normal. A brain MRI study detected a partial herniation of the right precentral gyrus through a meningeal defect into the diploe, embedding corticospinal fibers. The patient underwent navigated craniotomy. Intraoperative neuromonitoring of motor function with transcranial electrical stimulation and direct cortical stimulation indicated the presence of motor cortex inside the encephalocele. Thus, the brain parenchyma was carefully released without resection to preserve motor function and, finally, a cranioplasty was performed. After a few months, the patient demonstrated considerable improvement in his left lower-limb function and, after 1 year, he had fully recovered. Intraoperative electrophysiological monitoring and mapping allowed for the determination of the best surgical strategy for the isolation of the encephalocele and correlated well with preoperative multimodal MRI.

Radiation dose to the operator during fluoroscopically guided spine procedures.

PURPOSE: Fluoroscopy is widely used to guide diagnostic and therapeutic spine procedures. The purpose of this study was to quantify radiation incident on the operator (operator Air Kerma) during a wide range of fluoroscopy-guided spine procedures and its correlation with the amount of radiation incident on the patient (Kerma Area Product-KAP). METHODS: We retrospectively included 57 consecutive fluoroscopically guided spine procedures. KAP [Gy cm2] and total fluoroscopy time were recorded for each procedure. An electronic dosimeter recorded the operator Air Kerma [µGy] for each procedure. Operator Air Kerma for each procedure, correlation between KAP and operator Air Kerma, and between KAP and fluoroscopy time was obtained. RESULTS: Operator Air Kerma was widely variable across procedures, with median value of 6.4 µGy per procedure. Median fluoroscopy time and median KAP per procedure were 2.6 min and 4.7 Gy cm2, respectively. There was correlation between operator Air Kerma and KAP (r 2 = 0.60), with a slope of 1.6 µGy Air Kerma per unit Gy cm2 KAP incident on the patient and between fluoroscopy time and KAP (r 2 = 0.63). CONCLUSION: Operator Air Kerma during individual fluoroscopy-guided spine procedures can be approximated from the commonly and readily available information of the total amount of radiation incident on the patient, measured as KAP.

Functional connectivity MRI and post-operative language performance in temporal lobe epilepsy: initial experience.

Anterior temporal lobectomy is an effective treatment for drug-resistant epilepsy of temporal origin, although new language impairment may develop after surgery. Since correlations between functional connectivity (FC) MRI of the language network and verbal-IQ performance before surgery have recently been reported, we investigated the existence of correlations between the preoperative FC of the language network and post-operative verbal-IQ decline. FC between nodes of the language network of the two hemispheres (Interhemispheric-FC) and within nodes of the left hemisphere (LH-FC) and language lateralization indexes were estimated in five right-handed patients with non-tumoral left temporal lobe epilepsy undergoing anterior temporal lobectomy. Correlations between preoperative FC measures and lateralization indexes, and the post-operative (12 months) neuropsychological verbal-IQ decline were investigated. Verbal-IQ decline was inversely correlated with the degree of left lateralization and directly correlated with the strength of Interhemispheric-FC. No significant correlation was found between LH-FC and post-operative verbal-IQ change. The results from this limited number of patients suggest that a stronger preoperative connectivity between homologue regions, associated with the absence of a definite hemispheric lateralization, appears to be an unfavorable prognostic biomarker.

Data-driven grading of brain gliomas: a multiparametric MR imaging study.

PURPOSE: To grade brain gliomas by using a data-driven analysis of multiparametric magnetic resonance (MR) imaging, taking into account the heterogeneity of the lesions at MR imaging, and to compare these results with the most widespread current radiologic reporting methods. MATERIALS AND METHODS: One hundred eighteen patients with histologically confirmed brain gliomas were evaluated retrospectively. Conventional and advanced MR sequences (perfusion-weighted imaging, MR spectroscopy, and diffusion-tensor imaging) were performed. Three evaluations were conducted: semiquantitative (based on conventional and advanced sequences with reported cutoffs), qualitative (exclusively based on conventional MR imaging), and quantitative. For quantitative analysis, four volumes of interest were placed: regions with contrast material enhancement, regions with highest and lowest signal intensity on T2-weighted images, and regions of most restricted diffusivity. Statistical analysis included t test, receiver operating characteristic (ROC) analysis, discriminant function analysis (DFA), leave-one-out cross-validation, and Kendall coefficient of concordance. RESULTS: Significant differences were noted in age, relative cerebral blood volume (rCBV) in contrast-enhanced regions (cutoff > 2.59; sensitivity, 80%; specificity, 91%; area under the ROC curve [AUC] = 0.937; P = .0001), areas of lowest signal intensity on T2-weighted images (>2.45, 57%, 97%, 0.852, and P = .0001, respectively), restricted diffusivity regions (>2.61, 54%, 97%, 0.808, and P = .0001, respectively), and choline/creatine ratio in regions with the lowest signal intensity on T2-weighted images (>2.07, 49%, 88%, 0.685, and P = .0007, respectively). DFA that included age; rCBV in contrast-enhanced regions, areas of lowest signal intensity on T2-weighted images, and areas of restricted diffusivity; and choline/creatine ratio in areas with lowest signal intensity on T2-weighted images was used to classify 95% of patients correctly. Quantitative analysis showed a higher concordance with histologic findings than qualitative and semiquantitative methods (P < .0001). CONCLUSION: A quantitative multiparametric MR imaging evaluation that incorporated heterogeneity at MR imaging significantly improved discrimination between low- and high-grade brain gliomas with a very high AUC (ie, 0.95), thus reducing the risk of inappropriate or delayed surgery, respectively.

MRI neurography findings in patients with idiopathic brachial plexopathy: correlations with clinical-neurophysiological data in eight consecutive cases.

OBJECTIVE: Idiopathic brachial plexopathy is a non-progressive disorder characterized by the sudden onset of shoulder pain associated with weakness and sometimes paraesthesia of the arm. Clinical and electrophysiological examinations are the primary diagnostic tools and allow physicians to localize the site of damage. MRI neurography is rarely performed in this setting. METHODS: We herein describe the cases of eight consecutive patients suffering from idiopathic brachial plexopathy. All patients underwent clinical visits, neurophysiological evaluations and MRI neurography. RESULTS: We confirmed the primary role of clinical and neurophysiological evaluations in the diagnosis of idiopathic brachial plexopathy and demonstrate the usefulness of brachial plexus MRI neurography for confirming the presence of inflammatory changes. CONCLUSION: In patients with idiopathic brachial plexopathy, MR neurography is a helpful tool for excluding different aetiologies, such as compression or tumour formation, and/or confirming inflammatory changes.

Delayed hypothermia in malignant ischaemic stroke.

Moderate hypothermia may reduce mortality in malignant brain infarction. However, due to the extremely limited number of patients treated, it is still unknown whether it may be beneficial if undertaken several days after acute stroke, when the probability of a malignant oedema is higher. We report on a patient with malignant brain oedema after middle cerebral artery infarction, who was treated with moderate hypothermia on the third day after stroke when he became comatose. Hypothermia was induced at a rate of 1.25°C/h by an intravascular cooling catheter. The target temperature of 32°C was reached in about 6 h. After 36 h of hypothermia, the patient was actively re-warmed at a rate of 0.2°C/h. The patient survived and showed a progressive reduction of mass effect on CT scan. This single case study suggests a beneficial effect of hypothermia in the treatment of severe space-occupying ischemic infarction even on the third day after stroke onset.