Diagnosis, differential diagnosis and misdiagnosis of Susac syndrome.

BACKGROUND AND PURPOSE: Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common. METHODS: This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients. RESULTS: An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5-100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty-two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain-eye-ear involvement, 14 with brain-ear (44%), six with brain-eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1-9 months) compared to 5.25 months (range 0.5-100 months) for patients with encephalopathy and ocular symptoms at presentation. CONCLUSIONS: Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.

Tenecteplase vs Alteplase Before Endovascular Therapy in Basilar Artery Occlusion.

OBJECTIVE: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO). METHODS: To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion >50% or absence of retrievable thrombus at the time of the initial angiogram was evaluated. RESULTS: We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years; median NIH Stroke Scale score 16 [interquartile range (IQR) 7-32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion >50% occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3-12; p = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40-71] minutes) vs alteplase-treated patients (110 [IQR 51-185] minutes; p = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase; p = 0.9). CONCLUSIONS: TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted. CLINICALTRIALSGOV IDENTIFIERS: NCT02388061 and NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO.

Air vs. Road Decision for Endovascular Clot Retrieval in a Rural Telestroke Network.

Background and Purpose: Telestroke aims to increase access to endovascular clot retrieval (ECR) for rural areas. There is limited information on transfer workflow for ECR in rural settings. We sought to describe the transfer metrics for ECR in a rural telestroke network with respect to decision making. Methods: A retrospective cohort study was employed on consecutive patients transferred to the comprehensive stroke center (CSC) for ECR in a rural hub-and-spoke telestroke network between April 2013 and October 2019, by road or air. Key time-based metrics were analyzed. Results: Sixty-two patients were included. Mean age was 66 years [standard deviation (SD), 14] and median National Institutes of Health Stroke Scale 13 [interquartile range (IQR), 8-18]. Median rural-hospital-door-to-CSC-door (D2D) was 308 min (IQR, 254-351), of which 68% was spent at rural hospitals [door-in-door-out (DIDO); 214 min; IQR, 171-247]. DIDO was longer for air transfers than road (P = 0.004), primarily because of a median 87 min greater decision-to-departure time (Decision-DO, P < 0.001). In multiple linear regression analysis, intubation but not thrombolysis was associated with significantly longer DIDO. The distance at which the extra speed of an aircraft made up for the delays involved in booking an aircraft was 299 km from the CSC. Conclusions: DIDO is longer for air retrievals compared with road. Decision-DO represents the most important component of DIDO, being longer for air transfers. Systems for rapid transportation of rural ECR candidates need optimization for best patient outcomes, with decision support seen as a potential tool to achieve this.

The neuro-otology of Susac syndrome.

OBJECTIVE: We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. METHODS: The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. RESULTS: Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. CONCLUSIONS: Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

No Evidence of the "Weekend Effect" in the Northern New South Wales Telestroke Network.

Background: Admission outside normal business hours has been associated with prolonged door-to-treatment times and poorer patient outcomes, the so called "weekend effect. " This is the first examination of the weekend effect in a telestroke service that uses multi-modal computed tomography. Aims: To examine differences in workflow and triage between in-hours and out-of-hours calls to a telestroke service. Methods: All patients assessed using the Northern New South Wales (N-NSW) telestroke service from April 2013 to January 2019 were eligible for inclusion (674 in total; 539 with complete data). The primary outcomes measured were differences between in-hours and out-of-hours in door-to-call-to-decision-to-needle times, differences in the proportion of patients confirmed to have strokes or of patients selected for reperfusion therapies or patients with a modified Rankin Score (mRS ≤ 2) at 90 days. Results: There were no significant differences between in-hours and out-of-hours in any of the measured times, nor in the proportions of patients confirmed to have strokes (67.6 and 69.6%, respectively, p = 0.93); selected for reperfusion therapies (22.7 and 22.6%, respectively, p = 0.56); or independent at 3 months (34.8 and 33.6%, respectively, p = 0.770). There were significant differences in times between individual hospitals, and patient presentation more than 4.5 h after symptom onset was associated with slower times (21 minute delay in door-to-call, p = 0.002 and 22 min delay in door-to-image, p = 0.001). Conclusions: The weekend effect is not evident in the Northern NSW telestroke network experience, though this study did identify some opportunities for improvement in the delivery of acute stroke therapies.

What Is the "Optimal" Target Mismatch Criteria for Acute Ischemic Stroke?

We aimed to compare Perfusion Imaging Mismatch (PIM) and Clinical Core Mismatch (CCM) criteria in ischemic stroke patients to identify the effect of these criteria on selected patient population characteristics and clinical outcomes. Patients from the INternational Stroke Perfusion Imaging REgistry (INSPIRE) who received reperfusion therapy, had pre-treatment multimodal CT, 24-h imaging, and 3 month outcomes were analyzed. Patients were divided into 3 cohorts: endovascular thrombectomy (EVT), intravenous thrombolysis alone with large vessel occlusion (IVT-LVO), and intravenous thrombolysis alone without LVO (IVT-nonLVO). Patients were classified using 6 separate mismatch criteria: PIM-using 3 different measures to define the perfusion deficit (Delay Time, Tmax, or Mean Transit Time); or CCM-mismatch between age-adjusted National Institutes of Health Stroke Scale and CT Perfusion core, defined as relative cerebral blood flow <30% within the perfusion deficit defined in three ways (as above). We assessed the eligibility rate for each mismatch criterion and its ability to identify patients likely to respond to treatment. There were 994 patients eligible for this study. PIM with delay time (PIM-DT) had the highest inclusion rate for both EVT (82.7%) and IVT-LVO (79.5%) cohorts. In PIM positive patients who received EVT, recanalization was strongly associated with achieving an excellent outcome at 90-days (e.g., PIM-DT: mRS 0-1, adjusted OR 4.27, P = 0.005), whereas there was no such association between reperfusion and an excellent outcome with any of the CCM criteria (all p > 0.05). Notably, in IVT-LVO cohort, 58.2% of the PIM-DT positive patients achieved an excellent outcome compared with 31.0% in non-mismatch patients following successful recanalization (P = 0.006). Conclusion: PIM-DT was the optimal mismatch criterion in large vessel occlusion patients, combining a high eligibility rate with better clinical response to reperfusion. No mismatch criterion was useful to identify patients who are most likely response to reperfusion in non-large vessel occlusion patients.

Intravenous Thrombolysis May Not Improve Clinical Outcome of Acute Ischemic Stroke Patients Without a Baseline Vessel Occlusion.

Background and Purpose: The benefit of thrombolysis in ischemic stroke patients without a visible vessel occlusion still requires investigation. This study tested the hypothesis that non-lacunar stroke patients with no visible vessel occlusion on baseline imaging would have a favorable outcome regardless of treatment with alteplase. Methods: We utilized a prospectively collected registry of ischemic stroke patients [the International Stroke Perfusion Imaging Registry (INSPIRE)] who had baseline computed tomographic perfusion and computed tomographic angiography. The rates of patients achieving modified Rankin Scale (mRS) 0-1 were compared between alteplase treated and untreated patients using logistic regression to generate odds ratios. Results: Of 1569 patients in the INSPIRE registry, 1,277 were eligible for inclusion. Of these, 306 (24%) had no identifiable occlusion and were eligible for alteplase, with 141 (46%) of these patients receiving thrombolysis. The treated and untreated groups had significantly different median baseline National Institutes of Health Stroke Scale (NIHSS) [alteplase 8, interquartile range (IQR) 5-10, untreated 6, IQR 4-8, P < 0.001] and median volume of baseline perfusion lesion [alteplase 5.6 mL, IQR 1.3-17.7 mL, untreated 2.6 mL, IQR 0-6.7 mL, P < 0.001]. After propensity analysis, alteplase treated patients without a vessel occlusion were less likely to have an excellent outcome (mRS 0-1; 56%) than untreated (78.8%, OR, 0.42, 95% confidence interval, 0.24-0.75, P = 0.003). Conclusions: In this non-randomized comparison, alteplase treatment in patients without an identifiable vessel occlusion did not result in higher rates of favorable outcome compared to untreated. However, treated patients displayed less favorable baseline prognostic factors than the untreated group. Further studies may be required to confirm this data.

Validating a Predictive Model of Acute Advanced Imaging Biomarkers in Ischemic Stroke.

BACKGROUND AND PURPOSE: Advanced imaging to identify tissue pathophysiology may provide more accurate prognostication than the clinical measures used currently in stroke. This study aimed to derive and validate a predictive model for functional outcome based on acute clinical and advanced imaging measures. METHODS: A database of prospectively collected sub-4.5 hour patients with ischemic stroke being assessed for thrombolysis from 5 centers who had computed tomographic perfusion and computed tomographic angiography before a treatment decision was assessed. Individual variable cut points were derived from a classification and regression tree analysis. The optimal cut points for each assessment variable were then used in a backward logic regression to predict modified Rankin scale (mRS) score of 0 to 1 and 5 to 6. The variables remaining in the models were then assessed using a receiver operating characteristic curve analysis. RESULTS: Overall, 1519 patients were included in the study, 635 in the derivation cohort and 884 in the validation cohort. The model was highly accurate at predicting mRS score of 0 to 1 in all patients considered for thrombolysis therapy (area under the curve [AUC] 0.91), those who were treated (AUC 0.88) and those with recanalization (AUC 0.89). Next, the model was highly accurate at predicting mRS score of 5 to 6 in all patients considered for thrombolysis therapy (AUC 0.91), those who were treated (0.89) and those with recanalization (AUC 0.91). The odds ratio of thrombolysed patients who met the model criteria achieving mRS score of 0 to 1 was 17.89 (4.59-36.35, P<0.001) and for mRS score of 5 to 6 was 8.23 (2.57-26.97, P<0.001). CONCLUSIONS: This study has derived and validated a highly accurate model at predicting patient outcome after ischemic stroke.

Perfusion computed tomography in patients with stroke thrombolysis.

See Saver (doi:10.1093/awx020) for a scientific commentary on this article.Stroke shortens an individual's disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion computed tomography imaging variables (e.g. ischaemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. We used data from a prospectively collected international, multicentre, observational registry of acute ischaemic stroke patients who had perfusion computed tomography and computed tomography angiography before treatment with intravenous alteplase. Baseline perfusion computed tomography and follow-up magnetic resonance imaging were analysed to derive the baseline penumbra volume, baseline ischaemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on Disability-Adjusted Life Year. Clinical variables were age, sex, National Institutes of Health Stroke Scale score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate disability-adjusted life-year due to stroke, such that 1 year of disability-adjusted life-year equates to 1 year of healthy life lost due to stroke. There were 772 patients receiving alteplase therapy. The number of disability-adjusted life-year days lost per 1 ml of baseline ischaemic core volume was 17.5 (95% confidence interval, 13.2-21.9 days, P < 0.001). For every millilitre of penumbra salvaged, 7.2 days of disability-adjusted life-year days were saved (ß = -7.2, 95% confidence interval, -10.4 to -4.1 days, P < 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3-7.5 days, P = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in disability-adjusted life-year days. Pretreatment perfusion computed tomography can (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra, particularly when the ischaemic core is not too large.

Too good to treat? ischemic stroke patients with small computed tomography perfusion lesions may not benefit from thrombolysis.

OBJECTIVE: Although commonly used in clinical practice, there remains much uncertainty about whether perfusion computed tomography (CTP) should be used to select stroke patients for acute reperfusion therapy. In this study, we tested the hypothesis that a small acute perfusion lesion predicts good clinical outcome regardless of thrombolysis administration. METHODS: We used a prospectively collected cohort of acute ischemic stroke patients being assessed for treatment with IV-alteplase, who had CTP before a treatment decision. Volumetric CTP was retrospectively analyded to identify patients with a small perfusion lesion (<15ml in volume). The primary analysis was excellent 3-month outcome in patients with a small perfusion lesion who were treated with alteplase compared to those who were not treated. RESULTS: Of 1526 patients, 366 had a perfusion lesion <15ml and were clinically eligible for alteplase (212 being treated and 154 not treated). Median acute National Institutes of Health Stroke Scale score was 8 in each group. Of the 366 patients with a small perfusion lesion, 227 (62%) were modified Rankin Scale (mRS) 0 to 1 at day 90. Alteplase-treated patients were less likely to achieve 90-day mRS 0 to 1 (57%) than untreated patients (69%; relative risk [RR] = 0.83; 95% confidence interval [CI], 0.71-0.97; p = 0.022) and did not have different rates of mRS 0 to 2 (72% treated patients vs 77% untreated; RR, 0.93; 95% CI, 0.82-1.95; p = 0.23). INTERPRETATION: This large observational cohort suggests that a portion of ischemic stroke patients clinically eligible for alteplase therapy with a small perfusion lesion have a good natural history and may not benefit from treatment. Ann Neurol 2016;80:286-293.

Global White Matter Hypoperfusion on CT Predicts Larger Infarcts and Hemorrhagic Transformation after Acute Ischemia.

INTRODUCTION: Presence of white matter hyperintensity (WMH) on MRI is a marker of cerebral small vessel disease and is associated with increased small vessel stroke and increased risk of hemorrhagic transformation (HT) after thrombolysis. AIM: We sought to determine whether white matter hypoperfusion (WMHP) on perfusion CT (CTP) was related to WMH, and if WMHP predisposed to acute lacunar stroke subtype and HT after thrombolysis. METHODS: Acute ischemic stroke patients within 12 h of symptom onset at 2 centers were prospectively recruited between 2011 and 2013 for the International Stroke Perfusion Imaging Registry. Participants routinely underwent baseline CT imaging, including CTP, and follow-up imaging with MRI at 24 h. RESULTS: Of 229 ischemic stroke patients, 108 were Caucasians and 121 Chinese. In the contralateral white matter, patients with acute lacunar stroke had lower cerebral blood flow (CBF) and cerebral blood volume (CBV), compared to those with other stroke subtypes (P = 0.041). There were 46 patients with HT, and WMHP was associated with increased risk of HT (R(2) = 0.417, P = 0.002). Compared to previously reported predictors of HT, WMHP performed better than infarct core volume (R(2) = 0.341, P = 0.034), very low CBV volume (R(2) = 0.249, P = 0.026), and severely delayed perfusion (Tmax>14 second R(2) = 0.372, P = 0.011). Patients with WMHP also had larger acute infarcts and increased infarct growth compared to those without WMHP (mean 28 mL vs. 13 mL P < 0.001). CONCLUSION: White matter hypoperfusion remote to the acutely ischemic region on CTP is a marker of small vessel disease and was associated with increased HT, larger acute infarct cores, and greater infarct growth.

Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute ischemic stroke.

Whole-brain dynamic time-resolved computed tomography angiography (CTA) is a technique developed on the new 320-detector row CT scanner capable of generating time-resolved cerebral angiograms from skull base to vertex. Unlike a conventional cerebral angiogram, this technique visualizes pial arterial filling in all vascular territories, thereby providing additional hemodynamic information. Ours was a retrospective study of consecutive patients with ischemic stroke and M1 middle cerebral artery +/- intracranial internal carotid artery occlusions presenting to our center from June 2010 and undergoing dynamic time-resolved CTA and perfusion CT within 6 hours of symptom onset. Leptomeningeal collateral status was assessed by determining relative prominence of pial arteries in the ischemic region, rate and extent of retrograde flow, and various topographical patterns of pial arterial filling. Twenty-five patients were included in the study. We demonstrate the existence of the following novel properties of leptomeningeal collaterals in humans: (a) posterior (posterior cerebral artery (PCA)-MCA) dominant collateralization, (b) intra-territorial 'within MCA region' leptomeningeal collaterals, and (c) significant variability in size, extent, and retrograde filling time in pial arteries. We also describe a simple and reliable collateral grading template that, for the first time on dynamic CTA, incorporates back-filling time as well as size and extent of collateral filling.