Novel findings in a Swedish primary familial brain calcification cohort.

INTRODUCTION: Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. METHODS: Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. RESULTS: Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. CONCLUSIONS: This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.

Initial Clinical Images From a Second-Generation Prototype Silicon-Based Photon-Counting Computed Tomography System.

RATIONALE AND OBJECTIVES: To demonstrate the feasibility and potential of using a second-generation prototype photon-counting computed tomography (CT) system to provide simultaneous high spatial resolution images and high spectral resolution material information across a range of routine imaging tasks using clinical patient exposure levels. MATERIALS AND METHODS: The photon-counting system employs an innovative silicon-based photon-counting detector to provide a balanced approach to ultra-high-resolution spectral CT imaging. An initial cohort of volunteer subjects was imaged using the prototype photon-counting system. Acquisition technique parameters and radiation dose exposures were guided by routine clinical exposure levels used at the institution. Images were reconstructed in native slice thickness using an early version of a spectral CT reconstruction algorithm Samples of images across a range of clinical tasks were selected and presented for review. RESULTS: Clinical cases are presented across inner ear, carotid angiography, chest, and musculoskeletal imaging tasks. Initial reconstructed images illustrate ultra-high spatial resolution imaging. The fine detail of small structures and pathologies is clearly visualized, and structural boundaries are well delineated. The prototype system additionally provides concomitant spectral information with high spatial resolution. CONCLUSION: This initial study demonstrates that routine imaging at clinically appropriate patient exposure levels is feasible using a novel deep-silicon photon-counting detector CT system. Furthermore, a deep-silicon detector may provide a balanced approach to photon-counting CT, providing high spatial resolution imaging with simultaneous high-fidelity spectral information.

Timing of Antithrombotic Secondary Prevention in Patients with Intracranial Hemorrhage after Stroke Thrombolysis and Thrombectomy.

In patients with acute ischemic stroke, hemorrhagic transformation (HT) of infarcted tissue frequently occurs after reperfusion treatment. We aimed to assess whether HT and its severity influences the start of secondary prevention therapy and increases the risk of stroke recurrence. In this retrospective dual-center study, we recruited ischemic stroke patients treated with thrombolysis, thrombectomy or both. Our primary outcome was the time between revascularization and the start of any secondary prevention therapy. The secondary outcome was ischemic stroke recurrence within three months. We compared patients with vs. without HT and no (n = 653), minor (n = 158) and major (n = 51) HT patients using propensity score matching. The delay in the start of antithrombotics or anticoagulants was median 24 h in no HT, 26 h in minor HT and 39 h in major HT. No and minor HT patients had similar rates of any stroke recurrence (3.4% (all ischemic) vs. 2.5% (1.6% ischemic plus 0.9% hemorrhagic)). Major HT patients had a higher stroke recurrence at 7.8% (3.9% ischemic, 3.9% hemorrhagic), but this difference did not reach significance. A total of 22% of major HT patients did not start any antithrombotic treatment during the three-month follow-up. In conclusion, the presence of HT influences the timing of secondary prevention in ischemic stroke patients undergoing reperfusion treatments. Minor HT did not delay the start of antithrombotics or anticoagulants compared to no HT, with no significant difference in safety outcomes. Major HT patients remain a clinical challenge with both a delayed or lacking start of treatment. In this group, we did not see a higher rate of ischemic recurrence; however, this may have been censored by elevated early mortality. While not reaching statistical significance, hemorrhagic recurrence was somewhat more common in this group, warranting further study using larger datasets.

Performance of dual layer dual energy CT virtual monoenergetic images to identify early ischemic changes in patients with anterior circulation large vessel occlusion.

BACKGROUND AND PURPOSE: Dual energy CT is increasingly available and used in the standard diagnostic setting of ischemic stroke patients. We aimed to evaluate how different dual energy CT virtual monoenergetic energy levels impact identification of early ischemic changes, compared to conventional polyenergetic CT images. MATERIALS AND METHODS: This retrospective single-center study included patients presenting with acute ischemic stroke caused by an occlusion of the intracranial internal carotid artery or proximal middle cerebral artery. Data was gathered on consecutive patients admitted to our institution who underwent initial diagnostic stroke imaging with dual layer dual energy CT and a subsequent follow-up CT one to three days after admission. Automated ASPECTS results from conventional polyenergetic and different virtual monoenergetic energy level reconstructions at admission were generated and compared to reference standard ASPECTS. Confidence intervals (CI) for sensitivity, specificity, negative and positive predictive value were calculated. RESULTS: A total of 24 patients were included. Virtual monoenergetic reconstructions of 70 keV had the highest region-based ASPECTS accuracy, 0.90 (sensitivity 0.82 (95% CI 0.72-0.93), specificity 0.92 (0.88-0.97), negative predictive value 0.94 (0.90-0.96)), whereas virtual monoenergetic reconstructions of 40 keV had the lowest, 0.77 (sensitivity 0.34 (0.26-0.42), specificity 0.90 (0.89-0.96), negative predictive value 0.80 (0.77-0.83)). CONCLUSIONS: Automated 70 keV ASPECTS had the highest diagnostic accuracy, sensitivity and negative predictive value overall. Our results indicate that virtual monoenergetic energy levels impact the identification of early ischemic changes on CT.

Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort.

Background Neurologic complications in coronavirus disease 2019 (COVID-19) have been described, but the understanding of their pathophysiologic causes and neuroanatomical correlates remains limited. Purpose To report on the frequency and type of neuroradiological findings in COVID-19. Materials and Methods In this retrospective study, all consecutive adult hospitalized patients with polymerase chain reaction positivity for severe acute respiratory syndrome coronavirus 2 and who underwent neuroimaging at Karolinska University Hospital between March 2 and May 24, 2020, were included. All examinations were systematically re-evaluated by 12 readers. Summary descriptive statistics were calculated. Results A total of 185 patients with COVID-19 (62 years ± 14 [standard deviation]; 138 men) underwent neuroimaging. In total, 222 brain CT, 47 brain MRI, and seven spinal MRI examinations were performed. Intra-axial susceptibility abnormalities were the most common finding (29 of 39; 74%, 95% CI: 58, 87) in patients who underwent brain MRI, often with an ovoid shape suggestive of microvascular pathology and with a predilection for the corpus callosum (23 of 39; 59%; 95% CI: 42, 74) and juxtacortical areas (14 of 39; 36%; 95% CI: 21, 53). Ischemic and macrohemorrhagic manifestations were also observed, but vascular imaging did not demonstrate overt abnormalities. Dynamic susceptibility contrast perfusion MRI in 19 patients did not reveal consistent asymmetries between hemispheres or regions. Many patients (18 of 41; 44%; 95% CI: 28, 60) had leukoencephalopathy and one patient had a cytotoxic lesion of the corpus callosum. Other findings included olfactory bulb signal abnormalities (seven of 37; 19%), prominent optic nerve subarachnoid spaces (20 of 36; 56%), and enhancement of the parenchyma (three of 20; 15%), leptomeninges (three of 20; 15%), cranial nerves (two of 20; 10%), and spinal nerves (two of four; 50%). At MRI follow-up, regression of leukoencephalopathy and progressive leptomeningeal enhancement was observed in one patient each, respectively, which is suggestive of dynamic processes. Conclusion Patients with coronavirus disease 2019 had a wide spectrum of vascular and inflammatory involvement of both the central and peripheral nervous system. © RSNA, 2020 Online supplemental material is available for this article.

Dual-Energy CT Follow-Up After Stroke Thrombolysis Alters Assessment of Hemorrhagic Complications.

Background and Purpose: We aimed to determine whether dual-energy CT (DECT) follow-up can differentiate contrast staining (CS) from intracranial hemorrhage (ICH) in stroke patients treated with intravenous thrombolysis (IVT), who had undergone acute stroke imaging using CT angiography (CTA), and CT perfusion (CTP). Materials and Methods: Between November 2012 and January 2018, 168 patients at our comprehensive stroke center underwent DECT follow-up within 36 h after IVT and acute CTA with or without CTP but did not receive intra-arterial imaging or treatment. Two independent readers evaluated plain monochromatic CT (pCT) alone and compared this with a second reading of a combined DECT approach using pCT and water- and iodine-weighted images, establishing and grading the ICH diagnosis, per Heidelberg and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) classifications. Results: On pCT alone within 36 h, 31/168 (18.5%) patients had findings diagnosed as ICH. Using combined DECT (cDECT) changed ICH diagnosis to "CS only" in 3/168 (1.8%) patients, constituting 3/31 (9.7%) of cases with initially pCT-diagnosed ICH. These three cases had pCT diagnoses of one SAH, one minor, and one more extensive petechial hemorrhage (hemorrhagic infarction types 1 and 2), respectively. pCT alone had a 100% sensitivity, 98% specificity, 90% positive predictive value (PPV), 100% negative predictive value (NPV), and 98% accuracy for any ICH, compared to the cDECT. Inter-reader agreement for ICH classification using pCT compared to DECT was weighted kappa 0.92 (95% CI 0.87-0.98) vs. 0.91 (0.85-0.95). Conclusion: Compared to pCT, DECT within 36 h after IV thrombolysis for acute ischemic stroke, changes the radiological diagnosis of post-treatment ICH to "CS only" in a small proportion of patients. Studies are warranted of whether the altered radiological reports have an impact on patient management, for example initiation timing of antithrombotic secondary prevention.

Feasibility of unconstrained three-material decomposition: imaging an excised human heart using a prototype silicon photon-counting CT detector.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the feasibility of unconstrained three-material decomposition in a human tissue specimen containing iodinated contrast agent, using an experimental multi-bin photon-counting silicon detector. It was further to evaluate potential added clinical value compared to a 1st-generation state-of-the-art dual-energy computed tomography system. MATERIALS AND METHODS: A prototype photon-counting silicon detector in a bench-top setup for x-ray tomographic imaging was calibrated using a multi-material calibration phantom. A heart with calcified plaque was obtained from a deceased patient, and the coronary arteries were injected with an iodinated contrast agent mixed with gelatin. The heart was imaged in the experimental setup and on a 1st-generation state-of-the-art dual-energy computed tomography system. Projection-based three-material decomposition without any constraints was performed with the photon-counting detector data, and the resulting images were compared with those obtained from the dual-energy system. RESULTS: The photon-counting detector images show better separation of iodine and calcium compared to the dual-energy images. Additional experiments confirmed that unbiased estimates of soft tissue, calcium, and iodine could be achieved without any constraints. CONCLUSION: The proposed experimental system could provide added clinical value compared to current dual-energy systems for imaging tasks where mix-up of iodine and calcium is an issue, and the anatomy is sufficiently small to allow iodine to be differentiated from calcium. Considering its previously shown count rate capability, these results show promise for future integration of this detector in a clinical CT scanner. KEY POINTS: • Spectral photon-counting detectors can solve some of the fundamental problems with conventional single-energy CT. • Dual-energy methods can be used to differentiate iodine and calcium, but to do so must rely on constraints, since solving for three unknowns with only two measurements is not possible. Photon-counting detectors can improve upon these methods by allowing unconstrained three-material decomposition. • A prototype photon-counting silicon detector with high count rate capability allows performing unconstrained three-material decomposition and qualitatively shows better differentiation of iodine and calcium than dual-energy CT.

Radiological evaluation in patients with clinical suspicion of cerebral venous sinus thrombosis presenting with nontraumatic headache - a retrospective observational study with a validation cohort.

BACKGROUND: Clinical suspicion of cerebral venous sinus thrombosis (CVST) is imprecise due to non-specific symptoms such as headache. The aim was to retrospectively assess the diagnostic value of nonenhanced CT (neCT) in patients with nontraumatic headache and clinically suspected CVST. METHODS: A retrospective consecutive series of patients referred 2013-2015 for radiology were evaluated. Eligible patients had nontraumatic headache and suspicion of CVST stated in the referral, investigated with CT venography (CTV) and nonenhanced CT (neCT). neCT scans were re-evaluated for the presence of CVST or other pathology. All CTVs were checked for the presence of CVST. The validation cohort consisted of 10 patients with nontraumatic CVT (2017-2019). RESULTS: Less than 1% (1/104) had a suspected thrombus on neCT, confirmed by subsequent CTV. The remaining 99% had a CTV excluding CVST. Eleven percent had other imaging findings explaining their symptoms. In the patient with CVST, the thrombosed dural sinus was high attenuating (maximum HU 89) leading to the suspicion of CVST confirmed by CTV. The validation cohort (n = 10) confirmed the presence of a high attenuating (HU > 65) venous structure in the presence of a confirmed thrombus in all patients presenting within 10 days (suspicion written in referral, 10%). CONCLUSIONS: Despite clinical suspicion, imaging findings of CVST in nontraumatic headache are uncommon. Evaluating neCT for high attenuation in dural sinuses, followed by CTV for confirmation in selected cases seems reasonable. CVST should be recognized by all radiologists and requires a high level of awareness when reading neCT for other indications.

Dual energy CT after stroke thrombectomy alters assessment of hemorrhagic complications.

OBJECTIVE: To determine whether dual energy CT with a combined approach (cDECT) using a plain noncontrast monochromatic CT (pCT), a water-weighted image after iodine removal, and an iodine-weighted image changes the diagnosis and classification of intracranial hemorrhage (ICH) after endovascular thrombectomy (EVT) in acute ischemic stroke compared to a pCT image alone without separate water and iodine weighting. METHOD: During 2012 to 2016, 372 patients at our comprehensive stroke center underwent DECT scans within 36 hours after EVT. Two readers evaluated pCT compared to a second reading with cDECT, establishing the diagnosis of ICH and grading it per the Heidelberg and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) classifications. RESULT: Using cDECT changed the ICH diagnosis to contrast staining only in 34% (52 of 152), modified the ICH grade in 10% (15 of 152), and diagnosed initially undetected ICH in 2% (5 of 220). pCT alone had 95% sensitivity, 80% specificity, 66% positive predictive value, 98% negative predictive value, and 85% accuracy for ICH compared to cDECT. Interreader agreement on the presence of ICH increased with cDECT compared to pCT (Cohen κ = 0.77 [95% confidence interval 0.69-0.84] vs 0.68 [0.61-0.76]). CONCLUSION: cDECT within 36 hours after EVT changes the radiologic report regarding posttreatment ICH in a considerable proportion of patients undergoing EVT compared to pCT alone. This could affect decision-making regarding monitoring, secondary prevention, and prognostication. The cDECT scan could improve the interpretation consistency of high-attenuating changes on post-EVT images.

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization.

BACKGROUND AND AIMS: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. METHODS: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and low-calcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. RESULTS: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. CONCLUSIONS: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.

Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

Primary familial brain calcifications (PFBC) are a heterogeneous group of rare autosomal dominant disorders. Mutations in the PDGFB gene are the second most common cause of PFBC. A model for PDGFB-associated PFBC, hypomorphic PDGFB (ret/ret) mouse, displays impaired blood-brain barrier (BBB), progressive brain calcifications and increased flux of the oxysterol 24S-hydroxycholesterol from the brain into the circulation.(1,2) Only 8 families and 2 sporadic cases with PDGFB mutations have been identified so far, one of them a Swedish-Finnish family previously described as F13.(1,3-6) Very little is known about the natural history of PDGFB-associated PFBC. Here, we provide a comprehensive long-term follow-up of the F13 family.

The Stockholm 20-year follow-up of aneurysmal subarachnoid hemorrhage outcome.

OBJECTIVE: To assess the clinical and radiological long-term outcome after aneurysmal subarachnoid hemorrhage (SAH) in a defined referral area regarding recurrent SAH and de novo aneurysm formation. METHODS: One hundred and two 1-year survivors after aneurysmal SAH, who were treated at the Neurosurgical Clinic, South Hospital, Stockholm, Sweden, between 1983 and 1985, were followed for 20 years. Forty-nine surviving patients were reevaluated. Hospital records and death certificates were scrutinized for all 53 nonsurviving patients. Clinical history penetration, Mini Mental Status, Rankin Disability Score, and Barthel Index were used to evaluate the outcome. Computed tomographic angiography was used to investigate the cerebral arteries. RESULTS: One hundred and two patients were traced. Fifty-three patients were deceased. One patient had a hospital record of sustaining an aneurysmal SAH from a known but not clipped aneurysm. Three patients had nonaneurysmal intracerebral hemorrhage and two sustained traumatic SAH. There were 49 surviving patients. Six refused follow-up. None of these patients had hospital records of intracranial disease. Three of the 43 remaining patients could not be tested. None of the survivors had experienced a new SAH. Aneurysm base remnants were observed in 1% (eight patients, 790 person-years of follow-up) and de novo aneurysms were observed in 0.9% (seven patients, 790 person-years of follow-up). CONCLUSION: From this epidemiological survey of patients with aneurysmal SAH, it was found that none of the patients experienced a recurrent subarachnoid bleed from the treated aneurysm during a 20-year follow-up period. Thus, a routine extreme long-term follow-up period is not necessary. De novo aneurysm formation and possible enlargements of aneurysm base remnants were observed in almost 2% of patients per person year and should, therefore, be subject of a routine, long-term follow-up.