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Noninferiority trials aim to prove that the efficacy, defined in terms of a key clinical outcome, of a new treatment is not meaningfully worse than that of an established active control. Noninferiority trials are important when other aspects of care can be improved, such as convenience, toxicity, costs, and safety (nonefficacy benefits). While the motivation for a noninferiority trial is straightforward, the design, execution, and interpretation of these trials is not a trivial task. Several safeguards that protect superiority trials from incorrect conclusions do not apply or even work in reverse for noninferiority trials. This review aims to provide stroke clinicians and researchers with a general overview of noninferiority trials and a deeper understanding of 10 pitfalls they should consider when designing and interpreting such trials., Competing Interests: Dr Kaesmacher reports grants from Le Studium and grants from the Swiss National Science Foundation (SNSF) to other. Dr Saver reports stock options in Neuronics Medical; compensation from Biogen for consultant services; compensation from BrainQ for consultant services; compensation from Johnson & Johnson Health Care Systems, Inc, for consultant services; compensation from Roche for consultant services; stock options in MindRhythm; compensation from Stream Medical for consultant services; compensation from Bayer for consultant services; compensation from Medtronic USA, Inc, for consultant services; compensation from MIVI Neuroscience for data and safety monitoring services; compensation from CSL Behring for consultant services; compensation from Aeromics for consultant services; compensation from Boehringer Ingelheim (prevention only) for consultant services; compensation from Abbott Laboratories for consultant services; stock options in Rapid Medical; compensation from Occlutech for data and safety monitoring services; and compensation from BrainsGate for consultant services. Dr Gralla reports compensation from Johnson & Johnson Health Care Systems, Inc, for consultant services and compensation from Medtronic USA, Inc, for other services. Dr Fischer reports grants from Stryker to other; grants from Schweizerische Herzstiftung; grants from Penumbra, Inc, to other; grants from SNSF; compensation from phenox, Inc, for end point review committee services; grants from Medtronic to other; grants from phenox, Inc, to other; grants from Rapid Medical, Ltd, to other; grants from Boehringer Ingelheim; grants from Stryker to other; and grants from Medtronic to other. Dr Majoie reports grants from European Commission to other; grants from Health Evaluation Netherlands to other; grants from Stryker Corporation to other; stock holdings in Nicolab; grants from Dutch Heart Foundation to other; and grants from Boehringer Ingelheim to other. Dr Roos reports stock holdings in Nicolab. The other authors report no conflicts.

Background: Insight in differences in patient outcomes between endovascular thrombectomy (EVT) centers can help to improve stroke care. We assessed between-center variation in functional outcome of patients with acute ischemic stroke who were treated with EVT. We analyzed to what extent this variation may be explained by modifiable center characteristics., Methods: We used nationwide registry data of patients with stroke treated with EVT in the Netherlands and in the Czech Republic. Primary outcome was modified Rankin Scale score at 90 days as an indicator of disability. We used multilevel ordinal logistic regression to quantify the between-center variation in outcomes and the impact of patient and center characteristics. Between-center variation was expressed as the relative difference in odds of a more favorable modified Rankin Scale score between a relatively better performing center (75th percentile) and a relatively worse performing center (25th percentile)., Results: We included a total of 4518 patients treated in 33 centers. Adjusted for patient characteristics, the odds of a more favorable outcome in a center at the 75th percentile of the outcome distribution were 1.46 times higher (95% CI, 1.31-1.70) than the odds in a center at the 25th percentile. Adjustment for center characteristics, including the median time between stroke onset and reperfusion per center, decreased this relative difference in odds to 1.30 (95% CI, 1.18-1.50, P =0.01). This translates into an absolute difference in likelihood of good functional outcome of 8% after adjustment for patient characteristics and to 5% after further adjustment for modifiable center characteristics., Conclusions: The considerable between-center variation in patient outcomes after EVT for acute ischemic stroke could be largely explained by center-specific characteristics, such as time to reperfusion. Improvement of these parameters may likely result in a decrease in center-specific differences, and an overall improvement in outcome of patients with acute ischemic stroke.

Background and Purpose: Acute ischemic stroke due to large vessel occlusion is uncommon in young adults. We assessed stroke cause in young patients and compared their outcomes after endovascular thrombectomy with older patients., Methods: We used data (March 2014 until November 2017) of patients with an anterior circulation large vessel occlusion stroke from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a nationwide, prospective study on endovascular thrombectomy in the Netherlands. We compared young patients (18-49 years) with older patients (≥50 years). Outcomes included modified Rankin Scale score after 90 days (both shift and dichotomized analyses), expanded Thrombolysis in Cerebral Infarction score, and symptomatic intracranial hemorrhage. Analyses were adjusted for confounding., Results: We included 3256 patients, 310 (10%) were 18 to 49 years old. Young patients had lower median National Institutes of Health Stroke Scale scores (14 versus 16, P <0.001) and less cardiovascular comorbidities than older patients. Stroke etiologies in young patients included carotid dissection (16%), cardio-embolism (15%), large artery atherosclerosis (10%), and embolic stroke of undetermined source (31%). Clinical outcome was better in young than older patients (acOR for modified Rankin Scale shift: 1.8 [95% CI, 1.5-2.2]; functional independence [modified Rankin Scale score 0-2] 61 versus 39% [adjusted odds ratio, 2.1 [95% CI, 1.6-2.8]); mortality 7% versus 32%, adjusted odds ratio, 0.2 [95% CI, 0.1-0.3]). Symptomatic intracranial hemorrhage occurred less frequently in young patients (3% versus 6%, adjusted odds ratio, 0.5 [95% CI, 0.2-1.00]). Successful reperfusion (expanded Thrombolysis in Cerebral Infarction Score 2b-3) did not differ between groups. Onset to reperfusion time was shorter in young patients (253 versus 255 minutes, adjusted B in minutes 12.4 [95% CI, 2.4-22.5])., Conclusions: Ten percent of patients with acute ischemic stroke undergoing endovascular thrombectomy were younger than 50. Cardioembolism and carotid dissection were common underlying causes in young patients. In one-third of cases, no cause was identified, indicating the need for more research on stroke cause in young patients. Young patients had better prognosis and lower risk of symptomatic intracranial hemorrhage than older patients.

Background: Cerebral white matter lesions (WMLs) have been associated with a greater risk of poor functional outcome after ischemic stroke. We assessed the relations between WML burden and radiological and clinical outcomes in patients treated with endovascular treatment in routine practice., Methods: We analyzed data from the MR CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands)—a prospective, multicenter, observational cohort study of patients treated with endovascular treatment in the Netherlands. WMLs were graded on baseline noncontrast computed tomography using a visual grading scale. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included early neurological recovery, successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b), futile recanalization (modified Rankin Scale score ≥3 despite successful reperfusion), and occurrence of symptomatic intracranial hemorrhage. We used multivariable logistic regression models to assess associations between WML severity and outcomes, taking the absence of WML on noncontrast computed tomography as the reference category., Results: Of 3180 patients included in the MR CLEAN Registry between March 2014 and November 2017, WMLs were graded for 3046 patients and categorized as none (n=1855; 61%), mild (n=608; 20%), or moderate to severe (n=588; 19%). Favorable outcome (modified Rankin Scale score, 0–2) was achieved in 838 patients (49%) without WML, 192 patients (34%) with mild WML, and 130 patients (24%) with moderate-to-severe WML. Increasing WML grades were associated with a shift toward poorer functional outcome in a dose-dependent manner (adjusted common odds ratio, 1.34 [95% CI, 1.13–1.60] for mild WML and 1.67 [95% CI, 1.39–2.01] for moderate-to-severe WML; Ptrend, <0.001). Increasing WML grades were associated with futile recanalization (Ptrend, <0.001) and were inversely associated with early neurological recovery (Ptrend, 0.041) but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage., Conclusions: An increasing burden of WML at baseline is associated with poorer clinical outcomes after endovascular treatment for acute ischemic stroke but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage.

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters., Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45-82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machine-learning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18-90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age - chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out., Results: HIV-positive individuals had greater brain-PAD score (mean ± SD 2.15 ± 7.79 years) compared to HIV-negative individuals (-0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures., Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To assess if HIV-infected patients on long-term successful combination antiretroviral therapy show cerebral blood flow (CBF) alterations in comparison with HIV-uninfected, otherwise similar controls. To explore whether such alterations are associated with HIV-associated cognitive impairment and to explore potential determinants of CBF alterations in HIV., Design: Cross-sectional comparison of CBF in an observational cohort study., Methods: Clinical, cognitive and MRI data of 100 middle-aged aviremic HIV-infected men on combination antiretroviral therapy and 69 HIV-uninfected controls were collected and compared. From pseudocontinuous arterial spin labeling MRI data, CBF-maps were calculated. The associations of mean gray matter CBF with clinical and cognitive parameters were explored in regression models, followed by a spatial delineation in a voxel-based analysis., Results: CBF was decreased in HIV-infected patients compared with HIV-uninfected controls (P = 0.02), adjusted for age, ecstasy use and waist circumference. Spatially distinct and independent effects of total gray matter volume and HIV-serostatus on CBF were found. Within the HIV-infected group, decreased CBF was associated with increased triglyceride levels (P = 0.005) and prior clinical AIDS (P = 0.03). No association between CBF and cognitive impairment was found., Conclusion: Decreased CBF was observed among HIV-infected patients, which was associated with both vascular risk factors as well as with measures of past immune deficiency. These results provide support for increased vascular disease in HIV-infected patients as represented by hemodynamic alteration, but without overt cognitive consequences within the current cohort of patients on long-term successful treatment.

Background and Purpose: A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect., Methods: For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ 2 test to assess treatment effect modification by CBS., Results: Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04-1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12-2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group., Conclusions: A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment., Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR1804. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758., (© 2016 American Heart Association, Inc.)

Background and Purpose: Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make., Methods: The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score., Results: Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30-2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97-3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51-3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes., Conclusions: We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent., Clinical Trial Registration: URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758., (© 2016 American Heart Association, Inc.)

Objectives: The objective of this study was to assess whether HIV-infected patients on long-term successful combination antiretroviral therapy (cART) have more extensive white matter hyperintensities (WMH) of presumed vascular origin compared with uninfected controls and whether these intensities are associated with cognitive impairment. Furthermore, we explored potential determinants of increased WMH load long-term suppressed HIV infection., Design: A cross-sectional comparison of WMH in an observational cohort., Methods: Clinical, cognitive, and MRI data were collected from 103 middle-aged, aviremic HIV-infected men on cART, and 70 HIV-uninfected, otherwise similar controls. In the MRI data, WMH load was quantified by automated approaches and qualitatively reviewed by an experienced neuroradiologist using the Fazekas scale., Results: HIV-infected men had an increased WMH load. Among HIV-infected patients, increased WMH load was independently associated with older age, higher DBP, higher D-dimer levels, and longer time spent with a CD4 cell count below 500 cells/μl. HIV-associated cognitive deficits were associated with increased WMH load., Conclusions: WMH are more extensive and associated with cognitive deficits in middle-aged, aviremic cART-treated HIV-infected men. The extent of WMH load was associated with both cardiovascular risk factors and past immune deficiency. As cognitive impairment in these same patients is also associated with these risk factors, this may suggest that in the setting of HIV, WMH, and cognitive deficits share a common cause. This supports the importance of optimizing cardiovascular risk management, and early, effective treatment of HIV infection.

Background and Purpose: The capillary index score (CIS) is based on the hypothesis that areas lacking capillary blush on pretreatment cerebral digital subtraction angiograms correspond to nonviable cerebral tissue., Methods: Pretreatment digital subtraction angiograms and post-treatment noncontrast enhanced computed tomographic scans from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) trial were evaluated for areas lacking capillary blush and with tissue hypodensity, respectively. Because the superior and middle zones of the CIS correspond to the 7 cerebral cortex regions of the Alberta Stroke Program Early CT (ASPECT) score, capillary blush was scored in these 2 zones (0-2), called sub-CIS, and compared with the ASPECT score in these 7 regions (0-7), called hypodensity score. The presence and extent of hypodensity were compared between sub-CIS zones with contingency tables and nonparametric comparisons between groups, respectively., Results: On the basis of a sample size of 50 subjects, 100% with sub-CIS <2 had the presence of hypodensity (hypodensity score ≥1) versus 57% for sub-CIS=2 (P=0.004). The extent of hypodensity (numeric hypodensity score) was significantly lower for sub-CIS=2 than 0 or 1 (P=0.02). For 42 subjects with revascularization data, the presence and extent of hypodensity were significantly lower for sub-CIS=2 plus good revascularization than for other combinations of sub-CIS and revascularization (P=0.02 and 0.01, respectively)., Conclusions: The absence of capillary blush on pretreatment digital subtraction angiogram seems to correspond to nonviable cerebral tissue. Successful revascularization reduces the chance of tissue hypodensity (infarction), when capillary blush is present., Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR number 1804. URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758., (© 2016 American Heart Association, Inc.)

Background: The aim of the current study was to assess the influence of anesthetic management on the effect of treatment in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN)., Methods: MR CLEAN was a multicenter, randomized, open-label trial of intra-arterial therapy (IAT) vs no IAT. The intended anesthetic management at the start of the procedure was used for this post hoc analysis. The primary effect parameter was the adjusted common odds ratio (acOR) for a shift in direction of a better outcome on the modified Rankin Scale (mRS) at 90 days, estimated with multivariable ordinal logistic regression analysis, which included a term for general anesthesia (GA)., Results: GA was associated with significant (p = 0.011) effect modification, resulting in estimated decrease of 51% (95% confidence interval [CI] 31%-86%) in treatment effect compared to non-GA. We found a shift in the distribution on the mRS in favor of non-GA compared to control group (acOR 2.18 [95% CI 1.49-3.20]). The shift in distribution between GA and control group was in a similar direction (acOR 1.12 [95% CI 0.71-1.78]) with loss of statistical significance., Conclusions: In this post hoc analysis, we found that the type of anesthetic management influences outcome following IAT. Only treatment without general anesthesia was associated with a significant treatment benefit in MR CLEAN., Classification of Evidence: This study provides Class II evidence that for patients with acute ischemic stroke undergoing IAT, mRS scores at 90 days improve only in patients treated without GA., (© 2016 American Academy of Neurology.)

Background and Purpose: Preclinical studies showed that thrombus permeability improves recombinant tissue-type plasminogen activator (r-tPA) efficacy. We hypothesize that thrombus permeability estimated from radiological imaging is associated with improved recanalization after treatment with intravenously administered r-tPA (r-tPA) and with better functional outcome., Methods: We assessed thrombus attenuation increase (TAI) in patients from the Dutch Acute Stroke Study with an occlusion of an intracranial artery on computed tomographic angiography. Patients were included within 9 hours after the stroke onset. After dichotomization of TAI as pervious or impervious, logistic regressions analyses were performed to estimate associations of intravenous r-tPA therapy with complete recanalization and with favorable functional outcome (modified Rankin Scale score of ≤2)., Results: Three hundred eight patients matched the inclusion criteria. The median TAI was 20.1 (interquartile range, 8.5-37.8) Hounsfield unit (HU). We found a significant increase in the odds of complete recanalization with increasing TAI for patients treated with intravenous r-tPA (P=0.030). One hundred thirty-one (42%) thrombi were classified as pervious with TAI of ≥23 HU. In patients with a pervious thrombus, complete recanalization was more frequent after treatment with intravenous r-tPA than after conservative treatment (odds ratio, 6.26; 95% confidence interval, 2.4-16.8; P<0.001). In patients with an impervious thrombus, the effect of intravenous r-tPA was not significant (odds ratio, 1.4; 95% confidence interval, 0.5-4.1; P=0.47). Favorable outcome was more common in patients with a pervious thrombi than without (odds ratio, 2.1; 95% confidence interval, 1.3-3.4; P=0.001)., Conclusions: Thrombus perviousness, as measured on computed tomography in the acute stage of ischemic stroke, is strongly associated with recanalization after intravenous r-tPA treatment and with favorable functional outcome., (© 2016 American Heart Association, Inc.)

Objective: To investigate the effect of intra-arterial treatment (IAT) on early recovery from aphasia in acute ischemic stroke. We hypothesized that the early effect of IAT on aphasia is smaller than the effect on motor deficits., Methods: We included patients with aphasia from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), in which 500 patients with a proximal anterior circulation stroke were randomized to usual care plus IAT (<6 hours after stroke, mainly stent retrievers) or usual care alone. We estimated the effect of IAT on the shift on the NIH Stroke Scale (NIHSS) item language and the NIHSS item motor arm at 24 hours and 1 week after stroke with multivariable ordinal logistic regression as a common odds ratio, adjusted for prognostic variables (acOR). Differences between the effect of IAT on aphasia and on motor deficits were tested in a multilevel model with a multiplicative interaction term., Results: Of the 288 patients with aphasia, 126 were assigned to IAT and 162 to usual care alone. The acOR for improvement of language score at 24 hours was 1.65 (95% confidence interval [CI] 1.05-2.60), and at 1 week 1.86 (95% CI 1.18-2.94). The acOR for improvement of motor deficit at 24 hours was 2.44 (95% CI 1.54-3.88), and at 1 week 2.32 (95% CI 1.43-3.77). The effect of IAT on language deficits was significantly different from the effect on motor deficits at 24 hours and 1 week (p = 0.005 and p = 0.011)., Conclusions: IAT results in better early recovery from aphasia than usual care alone. The early effect of IAT on aphasia is smaller than the effect on motor deficits., Classification of Evidence: This study provides Class II evidence that for patients with acute ischemic stroke IAT increases early recovery from aphasia and that the early effect on aphasia, as measured by the NIHSS, is smaller than the effect on motor deficits., (© 2016 American Academy of Neurology.)

Background and Purpose: The Stroke Imaging Research (STIR) group, the Imaging Working Group of StrokeNet, the American Society of Neuroradiology, and the Foundation of the American Society of Neuroradiology sponsored an imaging session and workshop during the Stroke Treatment Academy Industry Roundtable (STAIR) IX on October 5 to 6, 2015 in Washington, DC. The purpose of this roadmap was to focus on the role of imaging in future research and clinical trials., Methods: This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the US Food and Drug Administration to discuss STIR priorities in the light of an unprecedented series of positive acute stroke endovascular therapy clinical trials., Results: The imaging session summarized and compared the imaging components of the recent positive endovascular trials and proposed opportunities for pooled analyses. The imaging workshop developed consensus recommendations for optimal imaging methods for the acquisition and analysis of core, mismatch, and collaterals across multiple modalities, and also a standardized approach for measuring the final infarct volume in prospective clinical trials., Conclusions: Recent positive acute stroke endovascular clinical trials have demonstrated the added value of neurovascular imaging. The optimal imaging profile for endovascular treatment includes large vessel occlusion, smaller core, good collaterals, and large penumbra. However, equivalent definitions for the imaging profile parameters across modalities are needed, and a standardization effort is warranted, potentially leveraging the pooled data resulting from the recent positive endovascular trials., (© 2016 American Heart Association, Inc.)

Objective: The spectrum of risk factors for HIV-associated cognitive impairment is likely very broad and includes not only HIV/antiretroviral therapy-specific factors but also other comorbid conditions. The purpose of this current study was to explore possible determinants for decreased cognitive performance., Design and Methods: Neuropsychological assessment was performed on 103 HIV-1-infected men with suppressed viraemia on combination antiretroviral therapy for at least 12 months and 74 HIV-uninfected highly similar male controls, all aged at least 45 years. Cognitive impairment and cognitive performance were determined by multivariate normative comparison (MNC). Determinants of decreased cognitive performance and cognitive impairment were investigated by linear and logistic regression analysis, respectively., Results: Cognitive impairment as diagnosed by MNC was found in 17% of HIV-1-infected men. Determinants for decreased cognitive performance by MNC as a continuous variable included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4⁺ cell count. Determinants for cognitive impairment, as dichotomized by MNC, included cannabis use, prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2., Conclusion: Decreased cognitive performance probably results from a multifactorial process, including not only HIV-associated factors, such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms.

Cognitive impairment is very common in chronic kidney disease (CKD) and is strongly associated with increased mortality. This review article will discuss the pathophysiology of cognitive impairment in CKD, as well as the effect of dialysis and transplantation on cognitive function. In CKD, uremic toxins, hyperparathyroidism and Klotho deficiency lead to chronic inflammation, endothelial dysfunction and vascular calcifications. This results in an increased burden of cerebrovascular disease in CKD patients, who consistently have more white matter hyperintensities, microbleeds, microinfarctions and cerebral atrophy on magnetic resonance imaging scans. Hemodialysis, although beneficial in terms of uremic toxin clearance, also contributes to cognitive decline by causing rapid fluid and osmotic shifts. Decreasing the dialysate temperature and increasing total dialysis time limits these shifts and helps maintain cognitive function in hemodialysis patients. For many patients, kidney transplantation is the preferred treatment modality, because it reverses the underlying mechanisms causing cognitive impairment in CKD. These positive effects have to be balanced against the possible neurotoxicity of infections and immunosuppressive medications, especially glucocorticosteroids and calcineurin inhibitors. A limited number of studies have addressed the overall effect of transplantation on cognitive function. These have mostly found an improvement after transplantation, but have a limited applicability to daily practice because they have only included relatively young patients.

Background and Purpose: Preclinical studies showed that thrombi can be permeable and may, therefore, allow for residual blood flow in occluded arteries of patients having acute ischemic stroke. This perviousness may increase tissue oxygenation, improve thrombus dissolution, and augment intra-arterial treatment success. We hypothesize that the combination of computed tomographic angiography and noncontrast computed tomography imaging allows measurement of contrast agent penetrating a permeable thrombus, and it is associated with improved outcome., Methods: Thrombus and contralateral artery attenuations in noncontrast computed tomography and computed tomographic angiography images were measured in 184 Multicenter Randomized Clinical trial of Endovascular treatment of acute ischemic stroke in the Netherlands (MR CLEAN) patients with thin-slice images. Two quantitative estimators of the thrombus permeability were introduced: computed tomographic angiography attenuation increase (Δ) and thrombus void fraction (ε). Patients were dichotomized as having a pervious or impervious thrombus and associated with outcome, recanalization, and final infarct volume., Results: Patients with Δ≥10.9 HU (n=81 [44%]) and ε≥6.5% (n=77 [42%]) were classified as having a pervious thrombus. These patients were 3.2 (95% confidence interval, 1.7-6.4) times more likely to have a favorable outcome, and 2.5 (95% confidence interval, 1.3-4.8) times more likely to recanalyze, for Δ based classification, and similarly for ε. These odds ratios were independent from intravenous or intra-arterial treatment. Final infarct volume was negatively correlated with both perviousness estimates (correlation coefficient, -0.39 for Δ and -0.40 for ε)., Conclusions: This study shows that simultaneous measurement of thrombus attenuation in noncontrast computed tomography and computed tomographic angiography allows for quantification of thrombus perviousness. Thrombus perviousness is strongly associated with improved functional outcome, smaller final infarct volume, and higher recanalization rate., (© 2016 American Heart Association, Inc.)

Background and Purpose: Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN)., Methods: MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status., Results: We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7-6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0-2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7-2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1-8.7] for patients with absent collaterals (grade 0)., Conclusions: In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals., Clinical Trial Registration: URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively., (© 2016 American Heart Association, Inc.)

Background and Purpose: Venous flow in the downstream territory of an occluded artery may influence patient prognosis after ischemic stroke. Our aim was to study cortical venous filling (CVF) in a time-resolved manner with dynamic computed tomographic angiography and to assess the relationship with clinical outcome., Methods: Patients with a proximal middle cerebral artery occlusion underwent noncontrast CT and whole-brain CT perfusion/dynamic CT angiography within 9 hours after stroke-onset. We defined poor outcome as a modified Rankin Scale score of ≥3. Association between the extent and velocity of CVF and poor outcome at 3 months was analyzed with Poisson-regression. Prognostic value of optimal CVF (maximum opacification of cortical veins) in addition to age, stroke severity, treatment, Alberta Stroke Program Early CT score, cerebral blood flow, and collateral status was assessed with logistic regression and summarized with the area under the curve., Results: Eighty-eight patients were included, with a mean age of 67 years. By combining the extent and velocity of optimal CVF, we observed a decreased risk of poor outcome in patients with good and fast optimal CVF, risk ratio of 0.5 (95% confidence interval, 0.3-0.7). Extent and velocity of optimal CVF had additional prognostic value (area under the curve, 0.88; 95% confidence interval, 0.77-0.98; P<0.02) compared with a model without CVF information., Conclusions: The combination of extent and velocity of optimal CVF, as assessed with dynamic CT angiography, is useful to identify patients with acute middle cerebral artery stroke at higher risk of poor clinical outcome at 3-month follow-up., Clinical Trial Registration: URL: http://www.trialregister.nl/trialreg and http://www.clinicaltrials.gov. Unique identifier: NTR1804 and NCT00880113, respectively., (© 2016 American Heart Association, Inc.)

Objective: The current study aims to evaluate the neurologic state of perinatally HIV-infected children on combination antiretroviral therapy and to attain a better insight into the pathogenesis of their persistent neurologic and cognitive deficits., Methods: We included perinatally HIV-infected children between 8 and 18 years and healthy controls matched for age, sex, ethnicity, and socioeconomic status. All participants underwent a 3.0 T MRI with 3D-T1-weighted, 3D-fluid-attenuated inversion recovery, and diffusion-weighted series for the evaluation of cerebral volumes, white matter hyperintensities (WMH), and white matter (WM) diffusion characteristics. Associations with disease-related parameters and cognitive performance were explored using linear regression models., Results: We included 35 cases (median age 13.8 years) and 37 controls (median age 12.1 years). A lower gray matter and WM volume, more WMH, and a higher WM diffusivity were observed in the cases. Within the HIV-infected children, a poorer clinical, immunologic, and virologic state were negatively associated with volumetric, WMH, and diffusivity markers., Conclusions: In children with HIV, even when long-term clinically and virologically controlled, we found lower brain volumes, a higher WMH load, and poorer WM integrity compared to matched controls. These differences occur in the context of a poor cognitive performance in the HIV-infected group, and larger, longitudinal studies are needed to increase our understanding of the pathogenesis of cerebral injury in perinatally HIV-infected children., (© 2015 American Academy of Neurology.)

Objective: Cognitive impairment is highly prevalent in HIV-1-infected (HIV+) patients, despite adequate suppression of viral replication by combination antiretroviral therapy (cART). Cerebral white matter structure alterations are often associated with cognitive impairment and have commonly been reported in the natural course of HIV infection. However, the existence of these alterations in adequately treated HIV+ patients remains unknown, as well as its possible association with cognitive impairment., Design: We used diffusion tensor imaging (DTI) to investigate whether white matter structure alterations exist in HIV+ patients with sustained suppressed viral replication on cART, and if such alterations are related to HIV-associated cognitive deficits., Methods: We compared 100 aviraemic HIV+ men on cART with 70 HIV-uninfected, otherwise comparable men. Clinical and neuropsychological assessments were performed. From DTI data, white matter fractional anisotropy and mean diffusion were calculated. Subsequently, tract-based spatial statistics (TBSS) was performed, with and without masking out white matter lesions., Results: HIV+ patients showed diffuse white matter structure alterations as compared with HIV-uninfected controls, observed as widespread decreased fractional anisotropy and an increased mean diffusion. These white matter structure alterations were associated with the number of years spent with a CD4 cell count below 500 cells/μl, but not with HIV-associated cognitive deficits., Conclusion: Cerebral white matter structure alterations are found in middle-aged HIV+ men with sustained suppression of viraemia on cART, and may result from periods with immune deficiency when viral toxicity and host-inflammatory responses were at their peak. These white matter structure alterations were not associated with the observed subtle HIV-associated cognitive deficits., Video Abstract: .

Background and Purpose: We assessed the effect of endovascular treatment in acute ischemic stroke patients with severe neurological deficit (National Institutes of Health Stroke Scale score, ≥20) after a prespecified analysis plan., Methods: The pooled analysis of the Interventional Management of Stroke III (IMS III) and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trials included participants with an National Institutes of Health Stroke Scale score of ≥20 before intravenous tissue-type plasminogen activator (tPA) treatment (IMS III) or randomization (MR CLEAN) who were treated with intravenous tPA ≤3 hours of stroke onset. Our hypothesis was that participants with severe stroke randomized to endovascular therapy after intravenous tPA would have improved 90-day outcome (distribution of modified Rankin Scale scores), when compared with those who received intravenous tPA alone., Results: Among 342 participants in the pooled analysis (194 from IMS III and 148 from MR CLEAN), an ordinal logistic regression model showed that the endovascular group had superior 90-day outcome compared with the intravenous tPA group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.66). In the logistic regression model of the dichotomous outcome (modified Rankin Scale score, 0-2, or functional independence), the endovascular group had superior outcomes (adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.56). Functional independence (modified Rankin Scale score, ≤2) at 90 days was 25% in the endovascular group when compared with 14% in the intravenous tPA group., Conclusions: Endovascular therapy after intravenous tPA within 3 hours of symptom onset improves functional outcome at 90 days after severe ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424 (IMS III) and ISRCTN10888758 (MR CLEAN)., (© 2015 American Heart Association, Inc.)

Background and Purpose: The utility of computed tomographic perfusion (CTP)-based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP. Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion., Methods: We included 175 patients who underwent CTP in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN). Association of CTP-derived parameters (ischemic-core volume, penumbra volume, and percentage ischemic core) with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale. Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. Interaction with treatment effect was also tested for mismatch (core <70 mL; penumbra core >1.2; penumbra core >10 mL)., Results: The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0.79 per 10 mL (95% confidence interval: 0.71-0.89; P<0.001), 0.82 per 10% (95% confidence interval: 0.66-0.90; P=0.002), and 0.97 per 10 mL (96% confidence interval: 0.92-1.01; P=0.15), respectively. No significant interaction between any of the CTP-derived parameters and treatment effect was observed. We observed no significant interaction between mismatch and treatment effect., Conclusions: CTP seems useful for predicting functional outcome, but cannot reliably identify patients who will not benefit from intra-arterial therapy., (© 2015 American Heart Association, Inc.)

Objective: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset., Methods: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache., Results: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%)., Conclusions: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting., (© 2015 American Academy of Neurology.)

Background and Purpose: Intra-arterial treatment (IAT) in patients with acute ischemic stroke (AIS) can be performed with or without general anesthesia (GA). Previous studies suggested that IAT without the use of GA (non-GA) is associated with better clinical outcome. Nevertheless, no consensus exists about the anesthetic management during IAT of AIS patients. This study investigates the association between type of anesthesia and clinical outcome in a large cohort of patients with AIS treated with IAT., Methods: All consecutive patients with AIS of the anterior circulation who received IAT between 2002 and 2013 in 16 Dutch hospitals were included in the study. Primary outcome was functional outcome on the modified Rankin Scale at discharge. Difference in primary outcome between GA and non-GA was estimated using multiple ordinal regression analysis, adjusting for age, stroke severity, occlusion of the internal carotid artery terminus, previous stroke, atrial fibrillation, and diabetes mellitus., Results: Three hundred forty-eight patients were included in the analysis; 70 patients received GA and 278 patients did not receive GA. Non-GA was significantly associated with good clinical outcome (odds ratio 2.1, 95% confidence interval 1.02-4.31). After adjusting for prespecified prognostic factors, the point estimate remained similar; statistical significance, however, was lost (odds ratio 1.9, 95% confidence interval 0.89-4.24)., Conclusions: Our study suggests that patients with AIS of the anterior circulation undergoing IAT without GA have a higher probability of good clinical outcome compared with patients treated with general anesthesia., (© 2015 American Heart Association, Inc.)

Objective: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH)., Methods: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging., Results: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0-8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p < 0.05), which was the only significant difference between groups., Conclusions: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients., (© 2015 American Academy of Neurology.)

Objective: The objective of this study is to assess whether multivariate normative comparison (MNC) improves detection of HIV-1-associated neurocognitive disorder (HAND) as compared with Frascati and Gisslén criteria., Methods: One-hundred and three HIV-1-infected men with suppressed viremia on combination antiretroviral therapy (cART) for at least 12 months and 74 HIV-uninfected male controls (comparable regarding age, ethnicity, sexual orientation, premorbid intelligence and educational level), aged at least 45 years, underwent neuropsychological assessment covering six cognitive domains (fluency, attention, information processing speed, executive function, memory, and motor function). Frascati and Gisslén criteria were applied to detect HAND. Next, MNC was performed to compare the cognitive scores of each HIV-positive individual against the cognitive scores of the control group., Results: HIV-infected men showed significantly worse performance on the cognitive domains of attention, information processing speed and executive function compared with HIV-uninfected controls. HAND by Frascati criteria was highly prevalent in HIV-infected [48%; 95% confidence interval (95% CI) 38-58] but nearly equally so in HIV-uninfected men (36%; 95% CI 26-48), confirming the low specificity of this method. Applying Gisslén criteria, HAND-prevalence was reduced to 5% (95% CI 1-9) in HIV-infected men and to 1% (95% CI 1-3) among HIV-uninfected controls, indicating better specificity but reduced sensitivity. MNC identified cognitive impairment in 17% (95% CI 10-24) of HIV-infected men and in 5% (95% CI 0-10) of the control group (P = 0.02, one-tailed), showing an optimal balance between sensitivity and specificity., Conclusion: Prevalence of cognitive impairment in HIV-1-infected men with suppressed viremia on cART estimated by MNC was much higher than that estimated by Gisslén criteria, while the false positive rate was greatly reduced compared with the Frascati criteria., Video Abstract: :

Background and Purpose: Aspirin early after intravenous thrombolysis in acute ischemic stroke increases the risk of symptomatic intracranial hemorrhage (SICH), without influencing functional outcome at 3 months. The effect of aspirin on early neurological deterioration (END) was explored as a post hoc analysis of the randomized Antiplatelet Therapy in Combination With Recombinant t-PA Thrombolysis in Ischemic Stroke (ARTIS) trial., Methods: END, defined as a ≥4 points National Institutes of Health Stroke Scale worsening ≤24 hours after intravenous thrombolysis, was categorized into SICH (ENDSICH) and cerebral ischemia (ENDCI). Multinomial logistic regression was used to assess the effect of aspirin on END., Results: Of the 640 patients, 31 patients (4.8%) experienced END (14 ENDSICH, 17 ENDCI). Aspirin increased the risk of ENDSICH (odds ratio, 3.73; 95% confidence interval, 1.03-13.49) but not of ENDCI (odds ratio, 1.14; 95% confidence interval, 0.44-3.00). After adjustment for other explanatory variables, the association between aspirin and ENDSICH remained significant., Conclusions: In this trial, there is no evidence of an early antithrombotic effect from the addition of aspirin to intravenous thrombolysis in acute ischemic stroke., (© 2014 American Heart Association, Inc.)

Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS)., Methods: fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation., Results: Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALS

Background: The reasons for development of intracranial aneurysms are unknown; hemodynamic factors may play an important role in this process. We performed a cohort study to further elicit the role of intracranial arterial geometry., Methods: We compared the original CTA/MRA of the circle of Willis of 26 patients who developed an aneurysm during follow-up with those of 78 controls with no aneurysm development who were matched for gender, age, and period of follow-up. We assessed hypoplasia of the arteries of the circle of Willis and measured bifurcation angles within and beyond the circle of Willis on three-dimensional CTA/MRA. Bifurcation angles were classified in tertiles for analysis. We used Student t test for comparison of bifurcation angles and calculated OR with corresponding 95% CI for presence of hypoplasia and bifurcation angles in tertiles., Results: A hypoplastic branch was found in 5 of 7 (71%) sites with aneurysm development and in 6 of 21 corresponding sites (29%) without aneurysm development (OR 6; 95%CI 0.9 to 42). The branch angle was sharp (lowest tertile) in 10 of 14 (71%) sites with aneurysm development and in 8 of 42 (19%) sites without aneurysm development (OR 11.3; 95% CI 2.0 to 64)., Conclusions: Bifurcations with a hypoplastic branch and bifurcations with sharper bifurcation angles are risk factors for development of aneurysms. Analysis of the geometry of intracranial arteries might be helpful in detecting persons with increased risk for developing aneurysms.

Objective: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS)., Methods: The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations., Results: Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation., Conclusions: MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.

Objective: To report late onset cerebral white matter disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD)., Background: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes., Methods: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies., Results: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination., Conclusions: Late-onset cerebral white matter disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease

A patient with neurofibromatosis type I and breast carcinoma developed a bilateral but asymmetric blepharospasm and paresis of the left abducens muscle over a 2-week course. MRI disclosed a small lesion in the left dorsomedial lower pontine region. Electrodiagnostic investigations revealed bilateral R1 responses after stimulation of the left supraorbital nerve and enhancement of R1 and R2 recovery curves. We concluded that lesions in the lower pontine tegmentum may cause blepharospasm.

A case of retrograde perineural tumor that spread from malignant melanoma of the face is reported. Contrast-enhanced CT and plain and contrast-enhanced MR studies, including fat suppression technique, showed tumor extension along the maxillary division of the trigeminal nerve. Histopathological examination of the surgical specimen revealed neurotropic malignant melanoma and confirmed the extent of tumor spread in the perineurium.