Endovascular Versus Medical Therapy in Posterior Cerebral Artery Stroke: Role of Baseline NIHSS Score and Occlusion Site.

BACKGROUND: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site. METHODS: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site (P1 versus P2), using multivariable regression modeling with interaction terms. The primary outcome was the favorable shift of 3-month modified Rankin Scale (mRS). Secondary outcomes included excellent outcome (mRS score 0-1), functional independence (mRS score 0-2), symptomatic intracranial hemorrhage, and mortality. RESULTS: From 1344 patients assessed for eligibility, 1059 were included (median age, 74 years; 43.7% women; 41.3% had intravenous thrombolysis): 364 receiving EVT and 695 receiving MM. Baseline stroke severity did not modify the association of EVT with 3-month mRS distribution (Pinteraction=0.312) but did with functional independence (Pinteraction=0.010), with a similar trend on excellent outcome (Pinteraction=0.069). EVT was associated with more favorable outcomes than MM in patients with baseline NIHSS score >6 (mRS score 0-1, 30.6% versus 17.7%; adjusted odds ratio [aOR], 2.01 [95% CI, 1.22-3.31]; mRS score 0 to 2, 46.1% versus 31.9%; aOR, 1.64 [95% CI, 1.08-2.51]) but not in those with NIHSS score ≤6 (mRS score 0-1, 43.8% versus 46.3%; aOR, 0.90 [95% CI, 0.49-1.64]; mRS score 0-2, 65.3% versus 74.3%; aOR, 0.55 [95% CI, 0.30-1.0]). EVT was associated with more symptomatic intracranial hemorrhage regardless of baseline NIHSS score (Pinteraction=0.467), while the mortality increase was more pronounced in patients with NIHSS score ≤6 (Pinteraction=0.044; NIHSS score ≤6: aOR, 7.95 [95% CI, 3.11-20.28]; NIHSS score >6: aOR, 1.98 [95% CI, 1.08-3.65]). Arterial occlusion site did not modify the association of EVT with outcomes compared with MM. CONCLUSIONS: Baseline clinical stroke severity, rather than the occlusion site, may be an important modifier of the association between EVT and outcomes in iPCAO. Only severely affected patients with iPCAO (NIHSS score >6) had more favorable disability outcomes with EVT than MM, despite increased mortality and symptomatic intracranial hemorrhage.

Delayed plasma kallikrein inhibition fosters post-stroke recovery by reducing thrombo-inflammation.

Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key component of the KKS - in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.

Performance fatigability in adults with spinal muscular atrophy treated long-term with nusinersen.

INTRODUCTION/AIMS: Persons with spinal muscular atrophy (pwSMA) report progressive muscle weakness but also reduced endurance when performing repetitive tasks in daily life, referred to as "performance fatigability" (PF). Data regarding the effects of the new disease-modifying drugs on PF are scarce. Thus, our main objective was to examine PF in adult ambulatory pwSMA treated long-term with nusinersen. METHODS: Six-minute walk test (6MWT) data from 14 adult pwSMA treated with nusinersen for up to 70 months were retrospectively analyzed to determine PF. Performance fatigability was defined as the percentage change in the distance covered between the last and first minute of the 6MWT. In addition, relationships between PF and other clinical features were assessed. RESULTS: Performance fatigability was found in 12/14 pwSMA (85.7%) prior to treatment. The mean distance walked in the sixth minute (71.1 m) was shorter than the distance covered in the first minute (81.8 m), corresponding to a mean PF of 13.1% (95% confidence interval (CI): 6.5-19.6, p = .0007). During treatment with nusinersen, there was a mean reduction in PF of 5.6% (95% CI: -10.0 to -1.3, p = .0148). We found no relationship between PF and fatigue as measured by the Fatigue Severity Scale. DISCUSSION: This study demonstrates the presence of PF as an independent component of motor impairment and as a potential therapeutic target in our cohort of adult ambulatory pwSMA. Furthermore, the observations in our cohort suggest that nusinersen may have a beneficial effect on PF.

Predictors and surgical outcome of hemorrhagic metastatic brain malignancies.

PURPOSE: Intracerebral metastases present a substantial risk of tumor-associated intracerebral hemorrhage (ICH). This study aimed to investigate the risk of hemorrhagic events in brain metastases (BM) from various primary tumor sites and evaluate the safety and outcomes of surgical tumor removal. METHODS: A retrospective, single-center review of medical records was conducted for patients who underwent BM removal between January 2016 and December 2017. Patients with hemorrhagic BM were compared to those with non-hemorrhagic BM. Data on preoperative predictors, perioperative management, and postoperative outcomes were collected and analyzed. RESULTS: A total of 229 patients met the inclusion criteria. Melanoma metastases were significantly associated with preoperative hemorrhage, even after adjusting for confounding factors (p = 0.001). Poor clinical status (p = 0.001), larger tumor volume (p = 0.020), and unfavorable prognosis (p = 0.001) independently predicted spontaneous hemorrhage. Importantly, preoperative use of anticoagulant medications was not linked to increased hemorrhagic risk (p = 0.592). Surgical removal of hemorrhagic BM, following cessation of blood-thinning medication, did not significantly affect intraoperative blood loss, surgical duration, or postoperative rebleeding risk (p > 0.096). However, intra-tumoral hemorrhage was associated with reduced overall survival (p = 0.001). CONCLUSION: This study emphasizes the safety of anticoagulation in patients with BM and highlights the safety of neurosurgical treatment in patients with hemorrhagic BM when blood-thinning medication is temporarily paused. The presence of intra-tumoral hemorrhage negatively impacts survival, highlighting its prognostic significance in BM patients. Further research with larger cohorts is warranted to validate these findings and elucidate underlying mechanisms.

Impact of post-thrombectomy isolated subarachnoid hemorrhage on neurological outcomes in patients with anterior ischemic stroke - a retrospective single-center observational study.

PURPOSE: We aimed to investigate the impact of post-thrombectomy isolated subarachnoid hemorrhage (i-SAH) and other types of intracranial hemorrhage (o-ICH) on patient's neurological outcomes. METHODS: Stroke data from 2018 to 2022 in a tertiary care center were retrospectively analyzed. Patients with large vessel occlusion from ICA to M2 branch were included. Post-thrombectomy intracranial hemorrhages at 24 h were categorized with Heidelberg Bleeding Classification. Neurological impairment of patients was continuously assessed at admission, at 24 h, 48 h and 72 h, and at discharge. Predictors of i-SAH and o-ICH were assessed. RESULTS: 297 patients were included. i-SAH and o-ICH were found in 12.1% (36/297) and 11.4% (34/297) of patients. Overall, NIHSS of i-SAH patients at discharge were comparable to o-ICH patients (median 22 vs. 21, p = 0.889) and were significantly higher than in non-ICH patients (22 vs. 7, p < 0.001). i-SAH often resulted in abrupt deterioration of patient's neurological symptoms at 24 h after thrombectomy. Compared to non-ICH patients, the occurrence of i-SAH was frequently associated with worse neurological outcome at discharge (median NIHSS increase of 4 vs. decrease of 4, p < 0.001) and higher in-hospital mortality (41.7% vs. 23.8%, p = 0.022). Regardless of successful reperfusion (TICI 2b/3), the beneficial impact of thrombectomy appeared to be outweighed by the adverse effect of i-SAH. Incomplete reperfusion and shorter time from symptom onset to admission were associated with higher probability of i-SAH, whereas longer procedure time and lower baseline ASPECTS were predictive for o-ICH occurrence. CONCLUSION: Post-thrombectomy isolated subarachnoid hemorrhage is a common complication with significant negative impact on neurological outcome.

Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome - an exploratory study.

BACKGROUND: Susac syndrome (SuS) is a rare autoimmune disease that leads to hearing impairment, visual field deficits, and encephalopathy due to an occlusion of precapillary arterioles in the brain, retina, and inner ear. Given the potentially disastrous outcome and difficulties in distinguishing SuS from its differential diagnoses, such as multiple sclerosis (MS), our exploratory study aimed at identifying potential new SuS-specific neuroimaging markers. METHODS: Seven patients with a definite diagnosis of SuS underwent magnetic resonance imaging (MRI) at 7 Tesla (7T), including T2* weighted and quantitative susceptibility mapping (QSM) sequences. T2 weighted hyperintense lesions were analyzed with regard to number, volume, localization, central vein sign, T1 hypointensity, and focal iron deposits in the center of SuS lesions ("iron dots"). Seven T MRI datasets from the same institute, comprising 75 patients with, among others, MS, served as controls. RESULTS: The "iron dot" sign was present in 71.4% (5/7) of the SuS patients, compared to 0% in our control cohort. Thus, sensitivity was 71.4% and specificity 100%. A central vein sign was only incidentally detected. CONCLUSION: We are the first to demonstrate this type of "iron dot" lesions on highly resolving 7T T2*w and QSM images in vivo as a promising neuroimaging marker of SuS, corroborating previous histopathological ex vivo findings.

Risk factors for poor outcome after aneurysmal subarachnoid hemorrhage in patients with initial favorable neurological status.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating diagnosis. A poor outcome is known to be highly dependent on the initial neurological status. Our goal was to identify other parameters that favor the risk of complications and poor outcome in patients with aSAH and initially favorable neurologic status. METHODS: Consecutive aSAH cases treated at our hospital between 01/2003 and 06/2016 with the initial World Federation of Neurosurgical Societies grades I-III were included. Data on demographic characteristics, previous medical history, initial aSAH severity, and functional outcome after aSAH were collected. The study endpoints were the occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months after aSAH (modified Rankin scale > 3). RESULTS: In the final cohort (n= 582), the rate of cerebral infarction, in-hospital mortality, and unfavorable outcome was 35.1%, 8.1%, and 17.6% respectively. The risk of cerebral infarction was independently related to the presence of acute hydrocephalus (adjusted odds ratio [aOR]=2.33, p<0.0001), aneurysm clipping (aOR=1.78, p=0.003), and use of calcium channel blockers concomitant to nimodipine (aOR=2.63, p=0.002). Patients' age (>55 years, aOR=4.24, p<0.0001), acute hydrocephalus (aOR=2.43, p=0.036), and clipping (aOR=2.86, p=0.001) predicted in-hospital mortality. Baseline characteristics associated with unfavorable outcome at 6 months were age (aOR=2.77, p=<0.0001), Fisher grades III-IV (aOR=2.81, p=0.016), acute hydrocephalus (aOR=2.22, p=0.012), clipping (aOR=3.98, p<0.0001), admission C-reactive protein>1mg/dL (aOR=1.76, p=0.035), and treatment intervals (aOR=0.64 per-5-year-intervals, p=0.006). CONCLUSIONS: Although cerebral infarction is a common complication in aSAH individuals with favorable initial clinical condition, >80% of these patients show favorable long-term outcome. The knowledge of outcome-relevant baseline characteristics might help to reduce the burden of further complications and poor outcome in aSAH patients who tolerated the initial bleeding event well.

Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study.

BACKGROUND: The optimal management of patients with isolated posterior cerebral artery occlusion is uncertain. We compared clinical outcomes for endovascular therapy (EVT) versus medical management (MM) in patients with isolated posterior cerebral artery occlusion. METHODS: This multinational case-control study conducted at 27 sites in Europe and North America included consecutive patients with isolated posterior cerebral artery occlusion presenting within 24 hours of time last well from January 2015 to August 2022. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The coprimary outcomes were the 90-day modified Rankin Scale ordinal shift and ≥2-point decrease in the National Institutes of Health Stroke Scale. RESULTS: Of 1023 patients, 589 (57.6%) were male with median (interquartile range) age of 74 (64-82) years. The median (interquartile range) National Institutes of Health Stroke Scale was 6 (3-10). The occlusion segments were P1 (41.2%), P2 (49.2%), and P3 (7.1%). Overall, intravenous thrombolysis was administered in 43% and EVT in 37%. There was no difference between the EVT and MM groups in the 90-day modified Rankin Scale shift (aOR, 1.13 [95% CI, 0.85-1.50]; P=0.41). There were higher odds of a decrease in the National Institutes of Health Stroke Scale by ≥2 points with EVT (aOR, 1.84 [95% CI, 1.35-2.52]; P=0.0001). Compared with MM, EVT was associated with a higher likelihood of excellent outcome (aOR, 1.50 [95% CI, 1.07-2.09]; P=0.018), complete vision recovery, and similar rates of functional independence (modified Rankin Scale score, 0-2), despite a higher rate of SICH and mortality (symptomatic intracranial hemorrhage, 6.2% versus 1.7%; P=0.0001; mortality, 10.1% versus 5.0%; P=0.002). CONCLUSIONS: In patients with isolated posterior cerebral artery occlusion, EVT was associated with similar odds of disability by ordinal modified Rankin Scale, higher odds of early National Institutes of Health stroke scale improvement, and complete vision recovery compared with MM. There was a higher likelihood of excellent outcome in the EVT group despite a higher rate of symptomatic intracranial hemorrhage and mortality. Continued enrollment into ongoing distal vessel occlusion randomized trials is warranted.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Modifiable vascular risk factors in patients with cerebral and spinal cavernous malformations: a complete 10-year follow-up study.

BACKGROUND AND PURPOSE: The aim was to investigate the effect of modifiable vascular risk factors on the risk of first and recurrent bleeding for patients with a cavernous malformation (CM) of the central nervous system (CNS) over a 10-year period. METHODS: A retrospective review of our CM institutional database was performed spanning from 2003 to 2021. The inclusion criteria were non-missing serial magnetic resonance imaging studies and clinical baseline metrics such as vascular risk factors. The exclusion criteria were patients who underwent surgical CM removal and patients with less than a decade of follow-up. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative risk (10 years) of hemorrhage. RESULTS: Eighty-nine patients with a CM of the CNS were included. Our results showed a non-significant increased risk of hemorrhage during 10 years of follow-up in patients using nicotine (hazard ratio 2.11, 95% confidence interval 0.86-5.21) and in patients with diabetes (hazard ratio 3.25, 95% confidence interval 0.71-14.81). For the presence of modifiable vascular risk factors at study baseline different cumulative 10-year risks of bleeding were observed: arterial hypertension 42.9% (18.8%-70.4%); diabetes 66.7% (12.5%-98.2%); hyperlipidemia 30% (8.1%-64.6%); active nicotine abuse 50% (24.1%-76%); and obesity 22.2% (4%-59.8%). Overall cumulative (10-year) hemorrhage risk was 30.3% (21.3%-41.1%). CONCLUSIONS: The probability of hemorrhage in untreated CNS CM patients increases progressively within a decade of follow-up. None of the modifiable vascular risk factors showed strong indication for an influence on hemorrhage risk, but our findings may suggest a more aggressive course in patients with active nicotine abuse or suffering from diabetes.

Small intracranial aneurysms of the anterior circulation: A negligible risk?

BACKGROUND AND PURPOSE: According to the International Study of Unruptured Intracranial Aneurysms, small (<7 mm) unruptured intracranial aneurysms (IAs) of the anterior circulation (aC) carry a neglectable 5-year rupture risk. In contrast, some studies report frequencies of >20% of all ruptured IAs being small IAs of the aC. This contradiction was addressed in this study by analyzing the rates and risk factors for rupture of small IAs within the aC. METHODS: Of the institutional observational cohort, 1676 small IAs of the aC were included. Different demographic, clinical, laboratory, and radiographic characteristics were collected. A rupture risk score was established using all independent prognostic factors. The score performance was checked using receiver operating characteristic curve analysis. RESULTS: Of all registered small IAs of the aC, 20.1% were ruptured. The developed small IAs of the aC (SIAAC) score (range = -4 to +13 points) contained five major risk factors: IA location and size, arterial hypertension, alcohol abuse, and chronic renal failure. In addition, three putative protective factors were also included in the score: hypothyroidism, dyslipidemia, and peripheral arterial disease. Increasing rates of ruptured IA with increasing SIAAC scores were observed, from 0% (≤-1 points) through >50% (≥8 points) and up to 100% in patients scoring ≥12 points. The SIAAC score achieved excellent discrimination (area under the curveSIAAC  = 0.803) and performed better than the PHASES (Population,Hypertension, Age, Size of the aneurysm, Earlier SAH from another aneurysm, Site of aneurysm) score. CONCLUSIONS: Small IAs of the aC carry a considerable rupture risk. After external validation, the proposed rupture risk score might provide a basis for better decision-making regarding the treatment of small unruptured IAs of the aC.

Radiation dose and fluoroscopy time of aneurysm coiling in patients with unruptured and ruptured intracranial aneurysms as a function of aneurysm size, location, and patient age.

PURPOSE: Endovascular treatment of unruptured intracranial aneurysms (UIAs) requires a risk-benefit analysis and adherence to diagnostic reference levels (DRLs). The national DRL (250 Gy·cm2) is only determined for intracranial aneurysm coiling in general, including ruptured intracranial aneurysms (RIAs). This study aims to investigate the dose in the treatment of UIAs and RIAs separately. METHODS: In a retrospective study design, dose area product (DAP) and fluoroscopy time (FT) were assessed for all patients undergoing intracranial aneurysm coiling between 2010 and 2021. DRL was set as the 75th percentile of the dose distribution. A multivariable linear regression analysis was performed to investigate DAP and FT for the two groups, UIA and RIA adjusted for patient age, aneurysm size, and location. RESULTS: 583 (414 females, mean age 56.5 years, 311 UIAs) are included. In the overall population, DAP (median (IQR)) is 157 Gy·cm2 (108-217) with a median FT of 32.7 min (IQR 24.0-47.0). Local DRL is 183 Gy·cm2 for UIAs and 246 Gy·cm2 for RIAs. After adjustment for the other variables, the UIA and RIA groups have a significant effect on both DAP (p < 0.001; 95% CI - 68.432 - - 38.040) and FT (p < 0.001; 95% CI - 628.279 - - 291.254). In general, both DAP and FT increase significantly with patient age and aneurysm size, whereas the location of the aneurysm did not significantly change neither DAP (p = 0.171; 95% CI - 5.537-31.065) nor FT (p = 0.136; 95% CI - 357.391-48.508). CONCLUSION: Both aneurysm size and patient age were associated with increased DAP, whereas aneurysm location did not significantly change DAP or FT. The increased dose in patients with RIAs is likely equivalent to additional diagnostic cerebral four-vessel angiography performed in this group.

[Consensus recommendations on regional interdisciplinary standardization of MRI diagnostics for multiple sclerosis in the metropolitan area of Essen]. / Konsensusempfehlungen zur regionalen fächerübergreifenden Standardisierung der MRT-Diagnostik bei Multipler Sklerose im Großraum Essen.

Magnetic resonance imaging (MRI) is of exceptional importance in the diagnostics and monitoring of multiple sclerosis (MS); however, a close interdisciplinary cooperation between neurologists in private practice, (neuro)radiological practices, hospitals or specialized MS centers is only rarely established. In particular, there is a lack of standardized MRI protocols for image acquisition as well as established quality parameters, which guarantee the comparability of MRI records; however, this is a fundamental prerequisite for an effective application of MRI in the treatment of MS patients, e.g., for making the diagnosis or treatment monitoring. To address these challenges a group of neurologists and (neuro)radiologists developed a consensus proposal for standardization of image acquisition, interpretation and transmission of results and for improvement in interdisciplinary cooperation. This pilot project in the metropolitan area of Essen used a modified Delphi process and was based on the most up to date scientific knowledge. The recommendation takes the medical, economic, temporal and practical aspects of MRI in MS into consideration. The model of interdisciplinary cooperation between radiologists and neurologists with the aim of a regional standardization of MRI could serve as an example for other regions of Germany in order to optimize MRI for MS.

The cerebellum contributes to context-effects during fear extinction learning: A 7T fMRI study.

The cerebellum is involved in the acquisition and consolidation of learned fear responses. Knowledge about its contribution to extinction learning, however, is sparse. Extinction processes likely involve erasure of memories, but there is ample evidence that at least part of the original memory remains. We asked the question whether memory persists within the cerebellum following extinction training. The renewal effect, that is the reoccurrence of the extinguished fear memory during recall in a context different from the extinction context, constitutes one of the phenomena indicating that memory of extinguished learned fear responses is not fully erased during extinction training. We performed a differential AB-A/B fear conditioning paradigm in a 7-Tesla (7T) MRI system in 31 young and healthy men. On day 1, fear acquisition training was performed in context A and extinction training in context B. On day 2, recall was tested in contexts A and B. As expected, participants learned to predict that the CS+ was followed by an aversive electric shock during fear acquisition training. Skin conductance responses (SCRs) were significantly higher to the CS+ compared to the CS- at the end of acquisition. Differences in SCRs vanished in extinction and reoccurred in the acquisition context during recall indicating renewal. Fitting SCR data, a deep neural network model was trained to predict the correct shock value for a given stimulus and context. Event-related fMRI analysis with model-derived prediction values as parametric modulations showed significant effects on activation of the posterolateral cerebellum (lobules VI and Crus I) during recall. Since the prediction values differ based on stimulus (CS+ and CS-) and context during recall, data provide support that the cerebellum is involved in context-related recall of learned fear associations. Likewise, mean ß values were highest in lobules VI and Crus I bilaterally related to the CS+ in the acquisition context during early recall. A similar pattern was seen in the vermis, but only on a trend level. Thus, part of the original memory likely remains within the cerebellum following extinction training. We found cerebellar activations related to the CS+ and CS- during fear acquisition training which likely reflect associative and non-associative aspects of the task. Cerebellar activations, however, were not significantly different for CS+ and CS-. Since the CS- was never followed by an electric shock, the cerebellum may contribute to associative learning related to the CS, for example as a safety cue.

Long-term follow-up and health-related quality of life among cancer survivors with stage IEA orbital-type lymphoma after external photon-beam radiotherapy: Results from a longitudinal study.

We assessed the long-term outcomes and treatment-related adverse effects of patients with Stage I, "orbital-type" lymphomas that were uniformly treated with photons. All consecutive patients diagnosed with low-grade, Ann Arbor Stage IEA orbital lymphoma treated between 1999 and 2020 at our department were retrospectively reviewed. We excluded patients with exclusive conjunctival involvement, typically treated with en face electrons. In order to quantify radiotherapy related side effects we applied the CTCAE criteria, analyzed changes in visual acuity, quantified dry eye symptoms by use of the Ocular Surface Disease Index (OSDI) score and applied the EORTC QLQ-C30 questionnaire for quality of life (QoL) assessment. In total 66 eyes of 62 patients were irradiated with a median dose of 30.6 Gy. The median follow-up was 43.5 months. The predominant histological subtype were MALT lymphomas. No local failure occurred in this cohort. Of nine outfield relapses, six solely occurred in the contralateral eye. The 5- and 10- years distant progression free survival rates (PFS) were 81.4% and 63.5%. The 5- and 10-years overall survival rates were 85.1% and 71.9% without any tumor related death. Of the acute toxicities none was higher than CTCAE grade 1. The predominant late toxicities were dry eyes (21.2%) of CTCAE Grade <2 and radiation induced cataracts (19.7%). During long-term follow up the average visual acuity did not deteriorate. The global QoL was worst before treatment and improved significantly after 24 months (p = 0.007). External beam radiotherapy of "orbital-type" lymphomas with photons is an effective and gentle treatment option with excellent local control rates. From the high control rates the trend to use slightly lower total doses of 24-27 Gy with conventional fractionation is supported. As non-coplanar radiotherapy techniques improved and total doses can slightly be reduced, the current status of radiotherapy as first line therapy is provided.

Multiple cerebral cavernous malformations: Clinical course of confirmed, assumed and non-familial disease.

BACKGROUND AND PURPOSE: Analyze and compare the natural course of confirmed familial cerebral cavernous malformation (FCCM), assumed FCCM and non-familial multiple cerebral cavernous malformation (CCM) disease over a 5-year period. METHODS: Our institutional database was screened for patients with CCM admitted between 2003 and 2020. Patients with complete magnetic resonance imaging dataset, evidence of multiple CCM, clinical baseline characteristics, and follow-up examination were included. Patients were separated into confirmed familial cases, assumed familial cases or non-familial multiple cavernous malformations. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for hemorrhage and recurrent hemorrhage. RESULTS: A total of 238 patients with multiple CCM were analyzed; 90 individuals had a confirmed FCCM disease, 115 an assumed FCCM, and 33 were allocated to the non-FCCM group. Univariate Cox regression analysis identified intracerebral hemorrhage (ICH) as mode of presentation (p = 0.001) as a predictor for occurrence of recurrent hemorrhage during the 5-year follow-up (FU). The cumulative 5-year risk of (re)bleeding was 21.6% for the entire cohort, 30.7% for patients with ICH at diagnosis, 22.1% for those patients with a confirmed diagnosis of FCCM, 23.5% for those with an assumed FCCM, and 21% for the non-FCCM cases. CONCLUSIONS: FCCM patients with ICH at diagnosis are prone to develop rebleeding. During untreated 5-year FU, FCCM patients and patients with sporadic multiple CCM reveal an almost equal susceptibility for (re)hemorrhage. Moreover, confirmed, assumed and non-FCCM patients showed an equal cumulative 5-year risk of symptomatic ICH. The probability of hemorrhage tends to increase over time, particularly in cases with ICH at presentation.

Radiation exposure in the endovascular therapy of cranial and spinal dural arteriovenous fistula in the last decade: a retrospective, single-center observational study.

PURPOSE: This study aims to determine local diagnostic reference levels (DRLs) in the endovascular therapy (EVT) of patients with cranial and spinal dural arteriovenous fistula (dAVF). METHODS: In a retrospective study design, DRLs and achievable dose (AD) were assessed for all patients with cranial and spinal dAVF undergoing EVT (I) or diagnostic angiography (II). All procedures were performed at the flat-panel angiography-system Allura Xper (Philips Healthcare). Interventional procedures were differentiated according to the region of fistula and the type of procedure. RESULTS: In total, 264 neurointerventional procedures of 131 patients with dAVF (94 cranial, 37 spinal) were executed between 02/2010 and 12/2020. The following DRLs, AD, and mean values could be determined: for cranial dAVF (I) DRL 507.33 Gy cm2, AD 369.79 Gy cm2, mean 396.51 Gy cm2; (II) DRL 256.65 Gy cm2, AD 214.19 Gy cm2, mean 211.80 Gy cm2; for spinal dAVF (I) DRL 482.72 Gy cm2, AD 275.98 Gy cm2, mean 347.12 Gy cm2; (II) DRL 396.39 Gy cm2, AD 210.57 Gy cm2, mean 299.55 Gy cm2. Dose levels of EVT were significantly higher compared to diagnostic angiographies (p < 0.001). No statistical difference in dose levels regarding the localization of dAVF was found. CONCLUSION: Our results could be used for establishing DRLs in the EVT of cranial and spinal dAVF. Because radiation exposure to comparably complex interventions such as AVM embolization is similar, it may be useful to determine general DRLs for both entities together.

Ischemia-induced inflammation in arteriovenous malformations.

OBJECTIVE: The pathophysiology of development, growth, and rupture of arteriovenous malformations (AVMs) is only partially understood. However, inflammation is known to play an essential role in many vascular diseases. This feasibility study was conducted to investigate the expression of enzymes (cyclooxygenase 2 [COX-2] and NLRP3 [NOD-, LRR-, and pyrin domain-containing protein 3]) in the AVM nidus that are essential in their inflammatory pathways and to explore how these influence the pathophysiology of AVMs. METHODS: The study group comprised 21 patients with partially thrombosed AVMs. The cohort included 8 ruptured and 13 unruptured AVMs, which had all been treated microsurgically. The formaldehyde-fixed and paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 and NLRP3 (COX-2 clone: CX-294; NLRP3: ab214185). The authors correlated MRI and clinical data with immunohistochemistry, using the Trainable Weka Segmentation algorithm for analysis. RESULTS: The median AVM volume was 2240 mm3. The proportion of NLRP3-positive cells was significantly higher (26.23%-83.95%), compared to COX-2 positive cells (0.25%-14.94%, p < 0.0001). Ruptured AVMs had no higher expression of NLRP3 (p = 0.39) or COX-2 (p = 0.44), compared to nonruptured AVMs. Moreover, no patient characteristics could be reported that showed significant correlations to the enzyme expression. CONCLUSIONS: NLRP3 consistently showed an approximately 10-fold higher expression level than COX-2, making the inflammatory process in AVMs appear to be mainly associated with ischemic (NLRP3)-driven rather than with mechanical (COX-2)-driven inflammatory pathways. No direct associations between NLRP3 and COX-2 expression and radiological, standard histopathological, or patient characteristics were found in this cohort.

Radiographic markers of breast cancer brain metastases: relation to clinical characteristics and postoperative outcome.

OBJECTIVE: Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients' characteristics and overall survival (OS). METHODS: We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed. RESULTS: The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (< 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024). CONCLUSION: Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients.

The accuracy of clinical neck staging for p16-positive and negative oropharyngeal cancer and its therapeutic implications.

PURPOSE: Oropharyngeal squamous cell carcinoma (OPSCC) may be treated with primary surgery or primary (chemo)radiation. While surgery with concurrent neck dissection provides definitive pathological staging of the neck, non-surgical treatment relies on clinical staging for treatment planning. To assess the accuracy of clinical neck staging, we compared clinical to surgical staging after primary surgery in patients with p16-negative and p16-positive OPSCC. METHODS: Retrospective analysis of clinical, pathological, and oncologic outcome data of patients with OPSCC treated with primary surgery and bilateral neck dissection. Clinical and pathological nodal status were compared for p16-negative and p16-positive patients. Patients with occult metastatic disease were analyzed in detail. RESULTS: 95 patients were included. 60.5% of p16-negative patients and 66.6% of p16-positive patients had pathologically confirmed metastatic neck disease. p16-positive patients had improved 24-month recurrence-free survival compared to p16-negative patients at 93.3% vs. 69.6%. Pathological N-status differed from clinical N-status in 36.8% of p16-negative patients vs. 31.6% of p16-positive patients. Occult metastatic disease was more common in p16-negative patients at 18.4% vs. 8.8% for p16-positive patients. Clinical detection sensitivity for extranodal extension was low overall; sensitivity was 27.3% and specificity was 91.6% for p16-negative patients vs. 61.5% and 80.0% for p16-positive patients, respectively. CONCLUSION: Our data show a considerable degree of inaccuracy of clinical neck staging results in all OPSCC patients which needs to be taken into consideration during therapy planning. For p16-positive patients, these findings warrant attention in the context of therapy deintensification to avoid undertreatment.