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Metachromatic leukodystrophy is a neurodegenerative condition with a variable rate of progression that warrants more systematic investigation. In their natural history study of 98 patients with metachromatic leukodystrophy, Dr. Kehrer et al. summarize the prominent symptoms and age of symptom onset according to various forms of the illnesses (late infantile, early juvenile, late juvenile, and adult). In younger persons (under age 6 years), motor manifestations with or without cognitive impairment were common, whereas in late juvenile and adult forms, cognitive symptoms became increasingly common. Patients with earlier disease onset experienced more rapid progression. Dr. Michell-Robinson and Lepine hypothesize that arylsulfatase A activity (the defective enzyme in metachromatic leukodystrophy) and therefore buildup of toxic sulfatide levels might be related to the severity or progression of the illness. Because some older patients may also experience rapid declines, the investigators do not believe sulfatide toxicity to be the primary mediator of disease severity. They also emphasize the importance of motor system involvement as a driver of neurologic deterioration. Although there is much more to understand about this condition, it is clear now that motor symptom manifestations typically precede rapid disease progression. Metachromatic leukodystrophy is a neurodegenerative condition with a variable rate of progression that warrants more systematic investigation. In their natural history study of 98 patients with metachromatic leukodystrophy, Dr. Kehrer et al. summarize the prominent symptoms and age of symptom onset according to various forms of the illnesses (late infantile, early juvenile, late juvenile, and adult). In younger persons (under age 6 years), motor manifestations with or without cognitive impairment were common, whereas in late juvenile and adult forms, cognitive symptoms became increasingly common. Patients with earlier disease onset experienced more rapid progression. Dr. Michell-Robinson and Lepine hypothesize that arylsulfatase A activity (the defective enzyme in metachromatic leukodystrophy) and therefore buildup of toxic sulfatide levels might be related to the severity or progression of the illness. Because some older patients may also experience rapid declines, the investigators do not believe sulfatide toxicity to be the primary mediator of disease severity. They also emphasize the importance of motor system involvement as a driver of neurologic deterioration. Although there is much more to understand about this condition, it is clear now that motor symptom manifestations typically precede rapid disease progression.

Using prospectively collected data from their neurosurgical referral center, Dr. Hoeritzauer et al. summarize their observations regarding patients with cauda equina syndrome (CES), with and without imaging confirmation. Among patients in this cohort, 69% lacked radiographic evidence of cauda equina compression and were referred to as “scan-negative” (normal MRI) or “mixed” (root enhancement without cauda compression). History or presence of functional symptoms, along with normal patellar reflexes, more severe pain, and panic attack at presentation were associated with a “scan-negative” condition. It is of interest that disturbances of urine or bowel function were no less common among patients with “scan-negative” CES. Dr. Amelot and colleagues highlight the importance of follow-up and education for patients at risk of CES (e.g., those with pre-existing disk disease). They also suggest that patients with scan-negative CES may be vulnerable to underlying somatization or anxiety over the threat of possible neurologic dysfunction. In response, Dr. Hoeritzauer et al. affirm that even patients with “scan-negative” CES were followed for several years after their initial presentation to evaluate the cause of their symptoms. Furthermore, the investigators maintain the objective of their study was to determine risk factors for “scan-negative” vs “scan-positive” CES, which includes functional neurologic disease, medications, pain, and panic. The investigators have referred clinicians and patients to their fact sheet on “scan-negative” CES for more information. Professor Beucler also emphasizes the clinical presentation of CES typically begins with radicular pain, followed by motor and later bowel or bladder symptoms. Using prospectively collected data from their neurosurgical referral center, Dr. Hoeritzauer et al. summarize their observations regarding patients with cauda equina syndrome (CES), with and without imaging confirmation. Among patients in this cohort, 69% lacked radiographic evidence of cauda equina compression and were referred to as “scan-negative” (normal MRI) or “mixed” (root enhancement without cauda compression). History or presence of functional symptoms, along with normal patellar reflexes, more severe pain, and panic attack at presentation were associated with a “scan-negative” condition. It is of interest that disturbances of urine or bowel function were no less common among patients with “scan-negative” CES. Dr. Amelot and colleagues highlight the importance of follow-up and education for patients at risk of CES (e.g., those with pre-existing disk disease). They also suggest that patients with scan-negative CES may be vulnerable to underlying somatization or anxiety over the threat of possible neurologic dysfunction. In response, Dr. Hoeritzauer et al. affirm that even patients with “scan-negative” CES were followed for several years after their initial presentation to evaluate the cause of their symptoms. Furthermore, the investigators maintain the objective of their study was to determine risk factors for “scan-negative” vs “scan-positive” CES, which includes functional neurologic disease, medications, pain, and panic. The investigators have referred clinicians and patients to their fact sheet on “scan-negative” CES for more information. Professor Beucler also emphasizes the clinical presentation of CES typically begins with radicular pain, followed by motor and later bowel or bladder symptoms.

In their retrospective autopsy series of 35 former football and hockey players, Schwab and colleagues found that half (49%) had histopathologic evidence of chronic traumatic encephalopathy (CTE) based on 2015 NINDS consensus criteria. Among their findings, the investigators reported no significant association between CTE risk and surrogate markers for lifetime exposure to sport and aggressive role/style of play, although the study was limited by its small sample size. The investigators conclude that factors other than cumulative physical contact and injury insufficiently explain the risk of CTE. Dr. Mez and colleagues compared these results from their recently published autopsy series of 266 former football players, in which the odds of CTE increased by 30% for every year of football played. In their work, Mez et al. also report no effect of player position (similar to the results of Schwab et al.); however, Mez et al. indicate that the findings reported here were too underpowered to detect any significant relationship between CTE and position or exposure duration. Furthermore, comments by Mez as well as Dr. Dams-O’Connor highlight important limitations in selection of the independent variables, particularly that the surrogate marker for duration of exposure (age at retirement) inadequately captures preprofessional duration of play. Preprofessional exposure and head injury have been shown in some studies to pose considerable risk as injuries accumulate in the developing brains of children and adolescents. The investigators acknowledge the limitation in statistical power, but reiterate a major conclusion that even subjects with relatively brief exposure to contact sports remain at risk of this histopathologic diagnosis, whereas others with protracted exposure may not develop this brain pathology. In their retrospective autopsy series of 35 former football and hockey players, Schwab and colleagues found that half (49%) had histopathologic evidence of chronic traumatic encephalopathy (CTE) based on 2015 NINDS consensus criteria. Among their findings, the investigators reported no significant association between CTE risk and surrogate markers for lifetime exposure to sport and aggressive role/style of play, although the study was limited by its small sample size. The investigators conclude that factors other than cumulative physical contact and injury insufficiently explain the risk of CTE. Dr. Mez and colleagues compared these results from their recently published autopsy series of 266 former football players, in which the odds of CTE increased by 30% for every year of football played. In their work, Mez et al. also report no effect of player position (similar to the results of Schwab et al.); however, Mez et al. indicate that the findings reported here were too underpowered to detect any significant relationship between CTE and position or exposure duration. Furthermore, comments by Mez as well as Dr. Dams-O’Connor highlight important limitations in selection of the independent variables, particularly that the surrogate marker for duration of exposure (age at retirement) inadequately captures preprofessional duration of play. Preprofessional exposure and head injury have been shown in some studies to pose considerable risk as injuries accumulate in the developing brains of children and adolescents. The investigators acknowledge the limitation in statistical power, but reiterate a major conclusion that even subjects with relatively brief exposure to contact sports remain at risk of this histopathologic diagnosis, whereas others with protracted exposure may not develop this brain pathology.

OBJECTIVE: To characterize differences in disposition arrangement among rehab-eligible stroke patients at a Comprehensive Stroke Center before and during the COVID-19 pandemic. MATERIALS AND METHODS: We retrospectively analyzed a prospective registry for demographics, hospital course, and discharge dispositions of rehab-eligible acute stroke survivors admitted 6 months prior to (10/2019-03/2020) and during (04/2020-09/2020) the COVID-19 pandemic. The primary outcome was discharge to an inpatient rehabilitation facility (IRF) as opposed to other facilities using descriptive statistics, and IRF versus home using unadjusted and adjusted backward stepwise logistic regression. RESULTS: Of the 507 rehab-eligible stroke survivors, there was no difference in age, premorbid disability, or stroke severity between study periods (p>0.05). There was a 9% absolute decrease in discharges to an IRF during the pandemic (32.1% vs. 41.1%, p=0.04), which translated to 38% lower odds of being discharged to IRF versus home in unadjusted regression (OR 0.62, 95%CI 0.42-0.92, p=0.016). The lower odds of discharge to IRF persisted in the multivariable model (aOR 0.16, 95%CI 0.09-0.31, p

Traumatic brain injury (TBI) has a well-known association with cognitive impairment and dementia. Whether there is a differential risk of dementia after TBI based on sex, race, or ethnicity was the subject of the recently published retrospective cohort study by Dr. Kornblith et al. Using a 2% random sample of claims data from Veterans Health Administration systems databases (n = 999,640), investigators evaluated the cumulative incidence of all-cause dementia by age, sex, race, and ethnicity. They found a significant interaction between TBI and race for dementia, in which White veterans were at the highest risk for dementia diagnoses. Dr. Roberts affirms these findings are consistent with the literature on White vs Black NFL players, in which White athletes are diagnosed more frequently with postconcussion “dementia” and receive greater compensation for this disability. More importantly, Dr. Roberts emphasizes that this racial discrepancy in dementia diagnoses is not likely an indicator of differential disease burden between races but is more reflective of racial care inequality. Dr. Kornblith agrees that racial disparities in health care are ubiquitous and demand more than just our attention. They demand action. Traumatic brain injury (TBI) has a well-known association with cognitive impairment and dementia. Whether there is a differential risk of dementia after TBI based on sex, race, or ethnicity was the subject of the recently published retrospective cohort study by Dr. Kornblith et al. Using a 2% random sample of claims data from Veterans Health Administration systems databases (n = 999,640), investigators evaluated the cumulative incidence of all-cause dementia by age, sex, race, and ethnicity. They found a significant interaction between TBI and race for dementia, in which White veterans were at the highest risk for dementia diagnoses. Dr. Roberts affirms these findings are consistent with the literature on White vs Black NFL players, in which White athletes are diagnosed more frequently with postconcussion “dementia” and receive greater compensation for this disability. More importantly, Dr. Roberts emphasizes that this racial discrepancy in dementia diagnoses is not likely an indicator of differential disease burden between races but is more reflective of racial care inequality. Dr. Kornblith agrees that racial disparities in health care are ubiquitous and demand more than just our attention. They demand action.

Using administrative claims data from 3 US states, Dr. Kuohn et al. report the long-term mortality rate of survivors with spontaneous intracerebral hemorrhage (ICH). Using an original population of 104,000 patients who were screened for eligibility, 72,432 survivors of the index hospitalization were followed for a median of 4 years. The 1-year risk of death or discharge to hospice was 9.5% (95% CI 9.2%–9.7%), with the most common proximate causes of death being infection (34%) or subsequent intracranial hemorrhage (13%). The median time from ICH to death was 10 months (IQR 2–31 months). Dr. Llamas-Nieves and colleagues highlight the importance of confounders such as diabetes, which was independently associated with death as shown in the multivariable regression model (HR 1.22, 95% CI 1.17–1.27), as this may be an important mediator of death because of infectious causes. The investigators acknowledge that diabetes contributes to death in the overall population; however, it was not independently associated with death due to infection (OR 1.16, 95% CI 0.86–1.55). The authors posit that diabetes (as well as age, post-ICH disability, and other comorbidities) are important contributors to the development of later infection, but it remains unclear why diabetes is not an independent modifier of death risk among patients who develop infection. Using administrative claims data from 3 US states, Dr. Kuohn et al. report the long-term mortality rate of survivors with spontaneous intracerebral hemorrhage (ICH). Using an original population of 104,000 patients who were screened for eligibility, 72,432 survivors of the index hospitalization were followed for a median of 4 years. The 1-year risk of death or discharge to hospice was 9.5% (95% CI 9.2%–9.7%), with the most common proximate causes of death being infection (34%) or subsequent intracranial hemorrhage (13%). The median time from ICH to death was 10 months (IQR 2–31 months). Dr. Llamas-Nieves and colleagues highlight the importance of confounders such as diabetes, which was independently associated with death as shown in the multivariable regression model (HR 1.22, 95% CI 1.17–1.27), as this may be an important mediator of death because of infectious causes. The investigators acknowledge that diabetes contributes to death in the overall population; however, it was not independently associated with death due to infection (OR 1.16, 95% CI 0.86–1.55). The authors posit that diabetes (as well as age, post-ICH disability, and other comorbidities) are important contributors to the development of later infection, but it remains unclear why diabetes is not an independent modifier of death risk among patients who develop infection.

Dr. Marzoughi and colleagues highlight the importance of personal visualization of neuroimaging and pursuit of advanced diagnostic testing in patients with severe headache and suspected intracranial lesions. In their case of an elderly gentleman with thunderclap headache and third nerve palsy, dedicated MRI with thin cuts through the sella identified pituitary apoplexy as the cause of the patient's symptoms. The fact that this patient exhibited brisk pupillary reactivity to light is somewhat atypical for a compressive third nerve palsy, as Professor Pollak comments. However, the authors indicate that the patient was anisocoric at presentation, with more pronounced asymmetry in bright light, meaning the ipsilateral parasympathetic pathway was dysfunctional. Furthermore, the pupillary fibers may be in a less vulnerable position in the cavernous sinus than in the subarachnoid space. Dr. Zhang et al. comment on other differential diagnoses for sudden, severe headache and cranial nerve palsies, which would include aneurysmal subarachnoid hemorrhage. In the absence of radiographic confirmation of a pituitary lesion—or other cause of thunderclap headache and cranial neuropathy (e.g., cavernous sinus thrombosis)—the clinician should pursue an occult aneurysm and/or subarachnoid hemorrhage as the cause of this patient's symptoms. Susceptibility-weighted and FLAIR MRI, conventional angiography, and lumbar puncture to evaluate for xanthochromia may be useful diagnostic tools when the cause of headache and cranial neuropathy(ies) remains elusive. Dr. Marzoughi and colleagues highlight the importance of personal visualization of neuroimaging and pursuit of advanced diagnostic testing in patients with severe headache and suspected intracranial lesions. In their case of an elderly gentleman with thunderclap headache and third nerve palsy, dedicated MRI with thin cuts through the sella identified pituitary apoplexy as the cause of the patient's symptoms. The fact that this patient exhibited brisk pupillary reactivity to light is somewhat atypical for a compressive third nerve palsy, as Professor Pollak comments. However, the authors indicate that the patient was anisocoric at presentation, with more pronounced asymmetry in bright light, meaning the ipsilateral parasympathetic pathway was dysfunctional. Furthermore, the pupillary fibers may be in a less vulnerable position in the cavernous sinus than in the subarachnoid space. Dr. Zhang et al. comment on other differential diagnoses for sudden, severe headache and cranial nerve palsies, which would include aneurysmal subarachnoid hemorrhage. In the absence of radiographic confirmation of a pituitary lesion—or other cause of thunderclap headache and cranial neuropathy (e.g., cavernous sinus thrombosis)—the clinician should pursue an occult aneurysm and/or subarachnoid hemorrhage as the cause of this patient's symptoms. Susceptibility-weighted and FLAIR MRI, conventional angiography, and lumbar puncture to evaluate for xanthochromia may be useful diagnostic tools when the cause of headache and cranial neuropathy(ies) remains elusive.

Background COVID-19 infection has been known to predispose patients to both arterial and venous thromboembolic events such as deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. A few reports from the literature suggest that Cerebral Venous Sinus Thrombosis (CVSTs) may be a direct complication of COVID-19. Objective To review the clinical and radiological presentation of COVID-19 positive patients diagnosed with CVST. Methods This was a multicenter, cross-sectional, retrospective study of patients diagnosed with CVST and COVID-19 reviewed from March 1, 2020 to November 8, 2020. We evaluated their clinical presentations, risk factors, clinical management, and outcome. We reviewed all published cases of CVST in patients with COVID-19 infection from January 1, 2020 to November 13, 2020. Results There were 8 patients diagnosed with CVST and COVID-19 during the study period at 7 out of 31 participating centers. Patients in our case series were mostly female (7/8, 87.5%). Most patients presented with non-specific symptoms such as headache (50%), fever (50%), and gastrointestinal symptoms (75%). Several patients presented with focal neurologic deficits (2/8, 25%) or decreased consciousness (2/8, 25%). D-dimer and inflammatory biomarkers were significantly elevated relative to reference ranges in patients with available laboratory data. The superior sagittal and transverse sinuses were the most common sites for acute CVST formation (6/8, 75%). Median time to onset of focal neurologic deficit from initial COVID-19 diagnosis was 3 days (interquartile range 0.75–3 days). Median time from onset of COVID-19 symptoms to CVST radiologic diagnosis was 11 days (interquartile range 6–16.75 days). Mortality was low in this cohort (1/8 or 12.5%). Conclusions Clinicians should consider the risk of acute CVST in patients positive for COVID-19, especially if neurological symptoms develop.

The American Heart Association/American Stroke Association guideline recommends maintaining blood pressure (BP) below 185/110 mm Hg in acute stroke patients prior to initiating any form of reperfusion therapy.1 However, the evidence supporting this recommendation is not strong for patients undergoing endovascular treatment (EVT). Higher BP at presentation in these patients is associated with worse outcomes and haemorrhagic complications.2 However, BP-lowering prior to EVT for avoidance of hyperperfusion as well as induced hypertension for penumbral sustenance have been proposed to improve patient outcomes.2 3 Prior to further testing of these strategies, whether changes in BP in either direction prior to EVT are associated with functional outcomes needs to be assessed. Because any changes in pre-EVT BP may affect ultimate functional outcome through an effect on cerebral perfusion, we aimed to determine the association of the change in pre-EVT mean arterial BP (MAP) with 90-day functional outcomes. We conducted a post-hoc analysis of the ‘Blood pressure after Endovascular Stroke Therapy (BEST)’ study, which prospectively enrolled consecutive adult patients treated with EVT for an anterior (Internal Carotid Artery/M1/M2) acute ischaemic stroke at 12 comprehensive stroke centres across the USA from November 2017 to May 2018.4 Study variables included change in MAP from admission to immediately pre-EVT. MAP was calculated using the following formula: (2×diastolic BP+systolic BP)/3. The primary outcome was dichotomous 90-day modified Rankin score …

BACKGROUND AND PURPOSE The 2018 AHA guidelines recommend perfusion imaging to select patients with acute large vessel occlusion (LVO) for thrombectomy in the extended window. However, the relationship between noncontrast CT and CT perfusion imaging has not been sufficiently characterized >6 hours after last known normal (LKN). METHODS From a multicenter prospective cohort of consecutive adults who underwent thrombectomy for anterior LVO 0-24 hours after LKN, we correlated baseline core volume (rCBF

BACKGROUND: Because of the overwhelming benefit of thrombectomy for highly selected trial patients with large vessel occlusion (LVO), some trial-ineligible patients are being treated in practice. OBJECTIVE: To determine the safety and efficacy of thrombectomy in DAWN/DEFUSE-3-ineligible patients. METHODS: Using a multicenter prospective observational study of consecutive patients with anterior circulation LVO who underwent late thrombectomy, we compared symptomatic intracerebral hemorrhage (sICH) and good outcome (90-d mRS 0-2) among DAWN/DEFUSE-3-ineligible patients to trial-eligible patients and to untreated DAWN/DEFUSE-3 controls. RESULTS: Ninety-eight patients had perfusion imaging and underwent thrombectomy >6 h; 46 (47%) were trial ineligible (41% M2 occlusions, 39% mild deficits, 28% ASPECTS

Background and Purpose— To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods— Consecutive adult patients treated with EVT for an anterior ischemic stroke were enrolled from November 2017 to July 2018 at 12 comprehensive stroke centers accross the United States. All SBP values within 24 hours post-EVT were recorded. Using Youden index, the threshold of peak SBP that best discriminated primary outcome of dichotomized 90-day modified Rankin Scale score (0–2 versus 3–6) was identified. Association of this SBP threshold with the outcomes was quantified using multiple logistic regression. Results— Among 485 enrolled patients (median age, 69 [interquartile range, 57–79] years; 51% females), a peak SBP of 158 mm Hg was associated with the largest difference in the dichotomous modified Rankin Scale score (absolute risk reduction of 19%). Having a peak SBP >158 mm Hg resulted in an increased likelihood of modified Rankin Scale score 3 to 6 (odds ratio, 2.24 [1.52–3.29], P P =0.28, after adjustment for prespecified variables). Conclusions— A peak post-EVT SBP of 158 mm Hg was prospectively identified to best discriminate good from bad functional outcome. Those with a peak SBP >158 had an increased likelihood of having a bad outcome in unadjusted, but not in adjusted analysis. The observed effect size was similar to prior studies. This finding should undergo further testing in a future randomized trial of goal-targeted post-EVT antihypertensive treatment.

Background: Palliative care improves quality of life in patients with malignancy; however, it may be underutilized in patients with high-grade gliomas (HGGs). We examined the practices regarding palliative care consultation (PCC) in treating patients with HGGs in the neurological intensive care unit (NICU) of an academic medical center. Methods: We conducted a retrospective cohort study of patients admitted to the NICU from 2011 to 2016 with a previously confirmed histopathological diagnosis of HGG. The primary outcome was the incidence of an inpatient PCC. We also evaluated the impact of PCC on patient care by examining its association with prespecified secondary outcomes of code status amendment to do not resuscitate (DNR), discharge disposition, 30-day mortality, and 30-day readmission rate, length of stay, and place of death. Results: Ninety (36% female) patients with HGGs were identified. Palliative care consultation was obtained in 16 (18%) patients. Palliative care consultation was associated with a greater odds of code status amendment to DNR (odds ratio [OR]: 18.15, 95% confidence interval [CI]: 5.01-65.73), which remained significant after adjustment for confounders (OR: 27.20, 95% CI: 5.49-134.84), a greater odds of discharge to hospice (OR: 24.93, 95% CI: 6.48-95.88), and 30-day mortality (OR: 6.40, 95% CI: 1.96-20.94). Conclusion: In this retrospective study of patients with HGGs admitted to a university-based NICU, PCC was seen in a minority of the sample. Palliative care consultation was associated with code status change to DNR and hospice utilization. Further study is required to determine whether these findings are generalizable and whether interventions that increase PCC utilization are associated with improved quality of life and resource allocation for patients with HGGs.

Objective To describe the prevalence and patterns of abnormal findings on automated computed tomography perfusion in patients with stroke mimic. Methods We reviewed a retrospective multi-site cohort of consecutive patients undergoing computed tomography perfusion for suspected acute ischemic stroke within 24 h from last normal (June 2017 to December 2017). The primary outcome was the diagnosis of stroke mimic. Hypoperfusion abnormalities on iSchemaView RAPID automated computed tomography perfusion were compared between patients with stroke/transient ischemic attack and stroke mimic using mixed-effects multivariable logistic regression, focusing on absence of perfusion abnormalities and discordance with clinical symptoms and computed tomography angiography findings. Results Of 410 consecutive patients who underwent computed tomography perfusion, 348 met inclusion criteria (178 (51%) stroke, 19 (6%) transient ischemic attack, and 151 (43%) mimic). Time-to-maximum of the tissue residue function (Tmax>6s) abnormalities were seen in 42 (28%) patients with stroke mimic and 122 (62%) patients with stroke/transient ischemic attack ( p max pattern (volume = 0mL; adjusted OR: 2.2, 95% CI: 1.1–4.3, p = 0.02). When the Tmax pattern was abnormal, a higher proportion of patients with stroke mimic had Tmax patterns fully discordant with clinical symptoms than patients with stroke/transient ischemic attack (28/39 (71%) vs. 10/115 (9%), p max abnormalities were strongly associated with stroke mimic (adjusted OR: 48.6, 95% CI: 7.0–336, p Conclusion While one-quarter of patients with stroke mimic show Tmax abnormalities on automated RAPID computed tomography perfusion imaging, the majority of patterns were discordant with symptoms and vessel status. Normal or fully discordant Tmax abnormalities are were more common with stroke mimic and may inform stroke treatment decision making.

Background and Purpose— The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods— Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%–49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results— Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39–1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86–1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63–8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73–1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54). Conclusions— In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

Embolic stroke of undetermined source (ESUS) accounts for about 20% of strokes. Nonstenotic cervical arterial plaque may be a mechanism of stroke in a subset of these patients.A cohort of consecutive patients with ischemic stroke was retrospectively identified from a stroke registry. Patients with unilateral anterior circulation embolic stroke due to atrial fibrillation (AF) or consistent with ESUS who underwent computed tomographic neck angiography were included. The prespecified primary outcome was a comparison of the prevalence of carotid plaque greater than or equal to 3 mm thickness ipsilateral versus contralateral to the infarct side.Of 772 screened patients, 96 patients with ESUS and 99 patients with AF were included. Plaque greater than or equal to 3 mm was more frequently ipsilateral than contralateral to the infarct in patients with ESUS (41% versus 29%, P = .03), and plaque thickness was greater ipsilateral compared to contralateral (median 2.5 versus 2.2 mm, P = .02). No significant differences in plaque characteristics ipsilateral compared to contralateral were found in patients with AF. The prevalence of ipsilateral versus contralateral plaque was greater in ESUS patients less than or equal to 65 years old (48% versus 19%, P.01), but no different in patients greater than 65 years old (35% versus 39%, P = .57).Nonstenotic cervical carotid plaque is more common ipislateral to the infarction in patients with ESUS, but not in patients with AF, supporting an underlying atheroembolic mechanism in a subset of ESUS patients. This association might be greater in younger ESUS patients.

Background and purpose Automated computed tomography perfusion (CTP) is recommended to inform selection of stroke patients for thrombectomy >6 hours from last known normal (LKN). However, artifacts on automated perfusion output may overestimate the tissue at risk leading to misclassification of thrombectomy eligibility in some patients. Methods We conducted a retrospective multisite study of consecutive patients with anterior large vessel occlusion (LVO) undergoing CTP (6/2017-12/2017). The primary outcome was the RAPID automated Tmax > 6 seconds volume that was discordant with clinical symptoms and vessel imaging, manually assessed by two independent readers. The discordant penumbral volume was compared to the automated output and corrected mismatch ratios were generated. Results Of 410 consecutive patients who underwent CTP for suspected stroke, 60 (15%) had acute anterior circulation LVO. Of these, 26 (43%) had Tmax > 6 seconds abnormalities discordant with clinical symptoms and vessel imaging. There was strong interrater agreement on artifact volume (r2 = 0.927). Among patients with discordant Tmax imaging, the median artifactual volume was 12cc (IQR 3-21cc), accounting for a median of 8% of the automated Tmax > 6 seconds volume (IQR 3-16%, range 1-64%). Recalculation of the Tmax > 6 seconds volume resulted in 1 patient being reclassified as having an "unfavorable" mismatch ratio (2.04-1.40). Conclusion Nearly half of patients had evidence of artifactual penumbral imaging on automated CTP, which rarely lead to misclassification of thrombectomy eligibility. Although artifactual findings are reliably identified by trained raters, our results emphasize the need to evaluate CTP results with knowledge of the patient's clinical symptoms and vascular imaging.

Background and Purpose: Early disability after stroke is common, though many patients improve. Stroke secondary prevention trials often prohibit the recruitment of nonambulatory patients, limiting their access to potential treatment options and impeding trial enrollment. We aimed to determine outcomes after early dependence around the time of transition from acute care to recovery. Methods: Data were obtained from a composite of patients enrolled in acute stroke clinical trials within the Virtual International Stroke Trials Archive (VISTA-Acute). Early disability was defined by the modified Rankin Scale (mRS) of 4 or 5 between days 3-10 after onset, representing the time of discharge or transition to a rehabilitation-focused care setting. We developed multivariable models to identify factors associated with recovery to independent ambulatory function and recurrent stroke during the 90 days after stroke. Results: 4965 patients were included, with 2905 (59%) having early disability. Patients with early dependence were older, more likely to be women, had higher baseline NIHSS scores, and had more atrial fibrillation and diabetes mellitus, compared with those who were initially ambulatory. Recovery to ambulatory function occurred in 58% with early mRS = 4, compared to only 16% with early mRS = 5. Of those with early mRS = 4, return to independent ambulatory status by 90 days was associated in multivariable analysis with age, diabetes, prior stroke, NIH motor and gaze subscores, and thrombolysis. Recurrent ischemic stroke through day 90 was reported in 126 of 2905 (4.3%) subjects with early dependence compared to 63 of 2060 (3.1%), which was not different after adjustment for age, sex, and risk factors (odds ratio 1.27; 95% confidence interval 0.92-1.73). Conclusions: Favorable outcomes are common among ischemic stroke patients previously enrolled in acute clinical trials despite early dependence (mRS = 4) after initial acute hospital care. Further, their risk of recurrent stroke is high in the short term. These patients likely benefit from aggressive poststroke care and should be actively recruited into secondary prevention trials.

A 73-year-old man with hypertension presented with left hemiparesis and left hemineglect of unclear duration. CT with angiography of the head and neck showed subacute infarcts of the right frontal lobe and a right internal carotid artery thrombus, with corresponding perfusion abnormalities that would have qualified him for thrombectomy (figure).1 On closer examination, his facial hair asymmetry suggested a matured hemineglect to his left face. Based on the unenhanced imaging findings and facial hair asymmetry, we estimated his stroke onset to be more than 24 hours prior to evaluation, thereby disqualifying him for thrombectomy.

Background: Automated computed tomography perfusion (CTP) is effective at identifying salvageable penumbra in patients with acute ischemic stroke due to large vessel occlusion (LVO). Perfusion imaging is now recommended for the selection of thrombectomy candidates in the extended window (>6 hours) which may incorporate the penumbra mismatch ratio (T max >6s:rCBF1.7. However automated perfusion output may include artifactual findings that are discordant with a patient’s symptoms and vessel imaging, overestimating the tissue at risk. Hypothesis: Artifactual findings on automated CTP penumbral assessment (T max >6s) will misclassify thrombectomy eligibility in some patients. Methods: We reviewed a retrospective multi-site consecutive cohort of patients undergoing CTP for suspected acute ischemic stroke ≤24 hours from onset (6/2017-12/2017). The primary outcome was the volume of any discordant T max >6s abnormality on RAPID automated perfusion CT imaging, calculated by two independent readers using manual assessment (ImageJ, NIH). The discordant penumbral volume was compared to the automated output and corrected mismatch ratios were generated. Results: Of 410 consecutive patients who underwent CTP, 60 (14.6%) had acute LVO of the anterior circulation and were included. The median age was 78 years (IQR 64-84), 36 (60.0%) were female, and 25 (41.7%) were White. Fifteen patients (26.3%) had T max >6s abnormalities that were discordant with the clinical symptoms or anticipated vascular distribution, with strong inter-rater agreement (r 2 =0.927). The median difference between manual and automated T max >6s volumes was 18.4cc (IQR 10.80-35.77) accounting for 11.3% of the automated volume (IQR 7.8-46.7%). Following manual recalculation of the T max >6s volume, 1 patient was reclassified as having an “unfavorable” mismatch ratio (1.7%, 95%CI 0.2-11.5%). Conclusion: About one quarter of patients had discordant penumbral imaging on automated CTP, which may lead to misclassification of thrombectomy eligibility. While artifactual findings are reliably identified by trained raters, our results emphasize the need to evaluate CTP results with knowledge of the patient’s clinical symptoms and vascular imaging.

Background: Automated computed tomography perfusion (CTP) imaging is proven effective at selecting patients with acute large vessel occlusion (LVO) for endovascular intervention in the extended time window (>6 hours after last known normal [LKN]). However, there are limited data on the likelihood of identifying core infarct-penumbral mismatch in the late time window. Hypothesis: Automated CTP mismatch ratios (Time-to-maximum residue function [T max ] >6s: relative cerebral blood flow [rCBF] Methods: We reviewed a retrospective registry of consecutive patients with LVO who underwent CTP within 24h of LKN at 3 academic hospitals between 06/2017 - 12/2017. Unenhanced CT and CTP parameters were compared between patients who presented within 12h of LKN versus 12-24h of LKN. Results: Among 60 included patients, the median age was 78 years (IQR 64-84), 36 (60.0%) were female, and 39 (65.0%) underwent thrombectomy. Patients who presented at 12-24h had poorer ASPECTS scores than patients who presented Conclusions: As time progresses in acute anterior LVO, the unenhanced CT may be more sensitive than rCBFFigure caption: ASPECTS and rCBF

Background: Recent data have demonstrated robust efficacy for endovascular thrombectomy in acute large vessel occlusion (LVO) up to 24h after symptom onset. Given the overwhelming benefit of this intervention in a highly selective, clinical trial population, it is plausible that a benefit may also be observed in some trial-ineligible patients. Methods: Using the BEST multi-center prospective cohort of consecutive patients who underwent thrombectomy for LVO, we compared DAWN and DEFUSE 3 trial-ineligible patients treated within 6-24 hours after last known normal (LKN) to trial-eligible patients, and to untreated controls from those trials. The co-primary outcomes were an early therapeutic response (decrease in NIHSS ≥10, or NIHSS 0-1 by 24h) and good functional outcome (90-day mRS 0-2). Secondary outcomes included change in NIHSS at 24h, intracerebral hemorrhage within 72h, and discharge to home or acute rehab. Results: Of 443 patients in the BEST cohort, 159 (36%) underwent endovascular therapy between 6-24 hours after LKN, of whom 71 (45%) were trial-ineligible. The most common trial exclusion criteria were M2 (53%) and multivessel occlusions (30%). Compared to trial-eligible patients, trial-ineligible patients were younger (median 63 vs. 72y, p=0.02) but had similar baseline NIHSS (median 14 vs. 15, p=0.28), ASPECTS scores (median 8 v. 8, p=0.69), times to recanalization (median 627 vs. 682 min, p=0.08), and rates of successful recanalization (TICI 2b/3, 83% v. 86%, p=0.57). Compared to DAWN untreated controls, BEST trial-ineligible patients were more likely to have an early therapeutic response (OR 2.02, 95%CI 1.00-4.06, p=0.049) and good functional outcome (OR 3.02, 95%CI 1.33-6.86, p=0.001). Compared to trial-eligible patients in BEST, trial-ineligible patients had similar improvements in 24h NIHSS (-2 vs. -4, p=0.33), rates of intracerebral hemorrhage (28% vs. 24%, p=0.54), and rates of discharge to home or rehab (77% vs. 73%, p=0.49). Conclusion: This multicenter prospective cohort demonstrates that thrombectomy for acute LVO within 24 hours in DAWN and DEFUSE 3 trial-ineligible patients is safe and may be effective. Treating these patients may be reasonable but our findings should be confirmed by additional randomized data trials.

Background: The 2018 AHA guidelines recommend patients with acute large vessel occlusion (LVO) be considered for thrombectomy in the 6 to 24-hour window based on perfusion imaging. Within 6 hours, CT perfusion (CTP) core estimates may underestimate volume of irreversible infarction visualized on the unenhanced CT; however this has not been well characterized in later time windows. Methods: Using a multi-center prospective cohort of consecutive patients who underwent thrombectomy for LVO 0-24 hours after last known normal, we correlated baseline CTP core infarct volume (rCBF Results: Of 443 enrolled patients, 165 who underwent CTP were included (median age 69y [IQR 57-80], 83 [50%] female, with a median ASPECTS of 8 [IQR 6-9] and core of 9cc [IQR 0-28]). ASPECTS and core volume moderately correlated (r=-0.35, p Conclusion: In this multi-center prospective cohort of patients who underwent thrombectomy, one-third of patients had normal core infarct volumes despite half of these patients showing irreversible infarction on the unenhanced CT (ASPECTS ≤8). As time progresses, the unenhanced CT demonstrates evolution of irreversible infarction, whereas the perfusion core appears static. This finding emphasizes the need to carefully assess both unenhanced CT and CTP when considering thrombectomy eligibility in the late time window, as was required by both DAWN and DEFUSE 3 selection criteria.

Background: One in 5 strokes have an embolic appearance but with no clear source (ESUS). Recent data have suggested anticoagulation is no better than antiplatelet therapy in preventing stroke recurrence in these patients, arguing against a cardioembolic mechanism. It is possible that non-stenotic cervical arterial plaque may be a mechanism of stroke in some patients with ESUS. Methods: A retrospective cohort of consecutive adults admitted with stroke to 3 hospitals was queried (08/2015 - 05/2017). Patients with acute, unilateral, anterior circulation infarcts who underwent CT angiography of the neck within 10 days of admission and were diagnosed with ESUS or a cardiac source of embolism (CE) were included, as determined by the modified TOAST criteria. The pre-specified primary outcome was moderate plaque (≥3mm), as defined in a recently published cohort of ESUS patients, and was compared between ipsi- and contra-lateral ICAs. Plaque features and degree of stenosis were secondary outcomes. Results: Of 786 screened patients, 97 patients with ESUS (12%) and 115 patients with CE (14%) were included. The median age was 71y (IQR 60-81) and 117 were female (54%). Moderate plaque was more frequently ipsilateral than contralateral to the infarct in patients with ESUS (42% vs. 30%, p McNemar =0.03) but not in CE (37% vs. 33%, p=0.53). There was no meaningful ICA stenosis for either side in the cohort (median stenosis 0% [IQR 0-10%]), nor was there a difference when sides were compared among patients with ESUS (median 0 vs. 0%, p=0.85) or patients with CE (0 vs. 0%, p=0.343). Conclusion: In this cohort, there was more moderate cervical ICA plaque ipsilateral to infarcts in patients with ESUS, but not in patients with CE, suggesting an underlying atherothromboembolic mechanism for some. As such, among ESUS patients, those with ipsilateral, non-stenotic ICA plaque may not benefit from anticoagulation compared to antiplatelet therapy to prevent recurrent stroke.

Background: Asymmetric internal carotid artery (ICA) plaque is common and are not fully explained by carotid geometry. Case reports have identified an increased risk of ICA injury and atherosclerosis with shorter hyoid wing-ICA distances. However, this relationship has not been characterized on a population level. Hypothesis: Shorter hyoid-ICA distances will be associated with greater ICA plaque and accelerated plaque formation over time. Methods: Retrospective cross-sectional and longitudinal cohort designs were used to evaluate consecutive adult patients at 3 hospitals who underwent 2 computed tomography angiography (CTA) studies of the neck ≥2 years apart (01/2000-07/2017). Patients with pre-existing neck or ICA surgery, dissection, or occlusion were excluded. Moderate ICA plaque (≥3mm), plaque characteristics, and stenosis at the level of the greater hyoid wing were compared by hyoid-ICA distance; and comparisons were made over time. Results: Sixty-six patients were included, with a median age of 64 years (IQR 53-73), 37 (56.1%) female, and 28 (42.4%) non-white. The median hyoid-ICA distance was 3.06mm (IQR 1.27-6.20mm), and when the hyoid-ICA distance was less than the median, moderate plaque was not more common (53.0% vs. 48.5%, p=0.601), and this remained non-significant after multivariable adjustment (OR 0.88, 95%CI 0.37-2.07, p=0.765) or when analyzed by hyoid-ICA distance quartile (adjusted p=0.586; Figure 1A). After a median follow-up of 1002 days (range 392-3,397 days), the odds of plaque progression (increase by ≥0.5mm) were not significantly greater when the hyoid-ICA distance was less than the median (adjusted OR 0.74, 95%CI 0.30-1.83, p=0.513), or when compared across distance quartiles (adjusted p=0.795; Figure 1B). Conclusion: In this cross-sectional and longitudinal cohort study, there was no association between hyoid wing proximity and ICA plaque thickness or stenosis.

In their retrospective analysis of 184 patients treated with intravenous thrombolysis for an unknown time of stroke onset, Macha et al. compared treatment times and outcomes based on assessment using multimodal computed tomography (CT) or magnetic resonance imaging (MRI). Unsurprisingly, patients selected for thrombolysis based on CT were treated more quickly than those who underwent brain MRI (mean difference 28 minutes); however, there were no significant differences in the rate of symptomatic intracranial hemorrhage or favorable outcome at 90 days between the imaging groups. Kumar and Singh comment that MRI has other advantages, such as the detection of microhemorrhages, higher spatial resolution for brain injury, lack of intravenous contrast requirement, and more rapid imaging acquisition with recent technological advancements. The investigators agree that MRI offers unique advantages over CT; however, these advantages are outweighed by the more expedient delivery of acute stroke care with CT, as has been confirmed in the recent EXTEND trial. Both the investigators and the commenters share optimism about the use of tenecteplase over alteplase as a means of shortening treatment delays; however, the safety and efficacy of tenecteplase beyond 4.5 hours (or in the unknown time window) have not yet been established. In their retrospective analysis of 184 patients treated with intravenous thrombolysis for an unknown time of stroke onset, Macha et al. compared treatment times and outcomes based on assessment using multimodal computed tomography (CT) or magnetic resonance imaging (MRI). Unsurprisingly, patients selected for thrombolysis based on CT were treated more quickly than those who underwent brain MRI (mean difference 28 minutes); however, there were no significant differences in the rate of symptomatic intracranial hemorrhage or favorable outcome at 90 days between the imaging groups. Kumar and Singh comment that MRI has other advantages, such as the detection of microhemorrhages, higher spatial resolution for brain injury, lack of intravenous contrast requirement, and more rapid imaging acquisition with recent technological advancements. The investigators agree that MRI offers unique advantages over CT; however, these advantages are outweighed by the more expedient delivery of acute stroke care with CT, as has been confirmed in the recent EXTEND trial. Both the investigators and the commenters share optimism about the use of tenecteplase over alteplase as a means of shortening treatment delays; however, the safety and efficacy of tenecteplase beyond 4.5 hours (or in the unknown time window) have not yet been established.

In their meta-analysis of 42 studies of patients with intracerebral hemorrhage (ICH, n = 26,174 patients), Jolink et al. report on the updated risk factors associated with lobar and nonlobar ICH. Hypertension remains an independent predictor of ICH, irrespective of location, whereas Black race, Hispanic ethnicity, male sex, diabetes, alcohol use, and underweight body habitus were also associated with nonlobar ICH. Zheng et al. comment that the effect of tobacco use may be underestimated in this meta-analysis and furthermore that the published data on tobacco use meet the Cochrane criteria for heterogeneity and thus may make their assessment on this issue unreliable. The readers also comment that the exclusion of one study from this meta-analysis would reduce the heterogeneity of included studies and yield a pooled effect estimate that indicates tobacco use is a statistically significant predictor of nonlobar ICH. The study investigators agree that the relationship between tobacco use and ICH may be underestimated, but they cannot exclude a study which meets criteria for inclusion. The heterogeneity of findings regarding tobacco use may be explained by varying definitions of tobacco use (never, remote, or current) and by differing amounts of use, which may contribute to a higher risk of ICH. However, based on the available data, the investigators conclude that there is insufficient evidence to support that tobacco use is associated with nonlobar ICH. In their meta-analysis of 42 studies of patients with intracerebral hemorrhage (ICH, n = 26,174 patients), Jolink et al. report on the updated risk factors associated with lobar and nonlobar ICH. Hypertension remains an independent predictor of ICH, irrespective of location, whereas Black race, Hispanic ethnicity, male sex, diabetes, alcohol use, and underweight body habitus were also associated with nonlobar ICH. Zheng et al. comment that the effect of tobacco use may be underestimated in this meta-analysis and furthermore that the published data on tobacco use meet the Cochrane criteria for heterogeneity and thus may make their assessment on this issue unreliable. The readers also comment that the exclusion of one study from this meta-analysis would reduce the heterogeneity of included studies and yield a pooled effect estimate that indicates tobacco use is a statistically significant predictor of nonlobar ICH. The study investigators agree that the relationship between tobacco use and ICH may be underestimated, but they cannot exclude a study which meets criteria for inclusion. The heterogeneity of findings regarding tobacco use may be explained by varying definitions of tobacco use (never, remote, or current) and by differing amounts of use, which may contribute to a higher risk of ICH. However, based on the available data, the investigators conclude that there is insufficient evidence to support that tobacco use is associated with nonlobar ICH.

We read with interest the results of the BEYOND-SWIFT retrospective observational registry by Meinel et al.1 Determination of candidacy for acute stroke intervention is a rapidly evolving and highly controversial field because we have seen in recently published trials, which are expanding eligibility criteria.

In their qualitative study of Johns Hopkins medical student experiences with challenging patient encounters, Willis and colleagues illustrate an important knowledge gap in medical student education. Among their findings, Willis's team reports that delivering bad news was a frequent challenge faced by medical students when speaking with patients. Furthermore, it appeared that over time (from second to fourth years of medical school), engaging in these tough conversations was no easier. In fact, over half of respondents indicated a lack of knowledge and experience in these difficult encounters, a major limitation of our education process. In response, Amin and Ullah reflect that the trainee–patient dynamic tends to improve with time and mentorship. Both the commenters and the investigators of this study agree that the challenges faced by medical students change with time because experience and confidence grow. However, the fact that trouble with difficult conversations persists throughout the last year of graduation highlights the need for continued mentorship, or a focused longitudinal curriculum on communication skills, to cultivate this important physician attribute. In their qualitative study of Johns Hopkins medical student experiences with challenging patient encounters, Willis and colleagues illustrate an important knowledge gap in medical student education. Among their findings, Willis's team reports that delivering bad news was a frequent challenge faced by medical students when speaking with patients. Furthermore, it appeared that over time (from second to fourth years of medical school), engaging in these tough conversations was no easier. In fact, over half of respondents indicated a lack of knowledge and experience in these difficult encounters, a major limitation of our education process. In response, Amin and Ullah reflect that the trainee–patient dynamic tends to improve with time and mentorship. Both the commenters and the investigators of this study agree that the challenges faced by medical students change with time because experience and confidence grow. However, the fact that trouble with difficult conversations persists throughout the last year of graduation highlights the need for continued mentorship, or a focused longitudinal curriculum on communication skills, to cultivate this important physician attribute.

Dr. Bar-Or and colleagues report the findings of the VELOCE multicenter randomized clinical trial, which evaluated the serologic response to vaccinations in patients with multiple sclerosis (MS) treated with the B-cell depleting agent, ocrelizumab. In this trial, patients with relapsing remitting MS were randomized to (1) ocrelizumab or (2) control (no disease modifying therapy or the use of interferon beta—which has limited effect against immunizations). The primary efficacy end point of a positive serologic response to tetanus toxoid was no different between the treatment or control groups, although control patients demonstrated a more robust response to immunization. The same serologic responses were observed between treatment groups using influenza, pneumococcal, and neoantigen vaccines. Nicole Hahn expresses concern regarding the sequence of the pneumococcal vaccinations, which is inconsistent with CDC recommendations. Dr. Bar-Or and colleagues explain that their approach (using PCV13 as a booster after PPSV23 at 4 weeks, rather than at a minimum of 8 weeks later) was intentionally used to evaluate T-cell dependent and independent pathways, rather than to evaluate the vaccination paradigm in patients with MS on ocrelizumab. Dr. Bar-Or and colleagues report the findings of the VELOCE multicenter randomized clinical trial, which evaluated the serologic response to vaccinations in patients with multiple sclerosis (MS) treated with the B-cell depleting agent, ocrelizumab. In this trial, patients with relapsing remitting MS were randomized to (1) ocrelizumab or (2) control (no disease modifying therapy or the use of interferon beta—which has limited effect against immunizations). The primary efficacy end point of a positive serologic response to tetanus toxoid was no different between the treatment or control groups, although control patients demonstrated a more robust response to immunization. The same serologic responses were observed between treatment groups using influenza, pneumococcal, and neoantigen vaccines. Nicole Hahn expresses concern regarding the sequence of the pneumococcal vaccinations, which is inconsistent with CDC recommendations. Dr. Bar-Or and colleagues explain that their approach (using PCV13 as a booster after PPSV23 at 4 weeks, rather than at a minimum of 8 weeks later) was intentionally used to evaluate T-cell dependent and independent pathways, rather than to evaluate the vaccination paradigm in patients with MS on ocrelizumab.

Using a propensity-matched cohort of >20,000 patients with acute ischemic stroke and >70,000 matched nonstroke individuals, Dr. Sposato et al. observed a 4-fold higher odds of major cardiac adverse events among patients with recent acute stroke. Importantly, patients were matched based on vascular risk factors, socioeconomic status, hospitalization frequency, and previous medications. The higher incidence of poststroke heart disease may have been related to the index cerebrovascular event, as the authors state. Alternatively, some patients may have experienced a stroke-induced myocardial stunning from excess sympathetic tone, which is supported by existing animal models and observational studies. Dr. Sioka et al. highlighted their own observations (using myocardial perfusion imaging) that subclinical coronary artery disease after stroke may be more common than expected. As noted by Dr. Sposato et al., the cohort reported by Sioka may have been selected for patients at risk of more coronary artery disease, given the stroke mechanisms and vascular profile of the included patients. Whatever the mechanism of myocardial injury, clinicians ought to monitor closely for concomitant cardiac disease among patients with recent cerebral infarction. Using a propensity-matched cohort of >20,000 patients with acute ischemic stroke and >70,000 matched nonstroke individuals, Dr. Sposato et al. observed a 4-fold higher odds of major cardiac adverse events among patients with recent acute stroke. Importantly, patients were matched based on vascular risk factors, socioeconomic status, hospitalization frequency, and previous medications. The higher incidence of poststroke heart disease may have been related to the index cerebrovascular event, as the authors state. Alternatively, some patients may have experienced a stroke-induced myocardial stunning from excess sympathetic tone, which is supported by existing animal models and observational studies. Dr. Sioka et al. highlighted their own observations (using myocardial perfusion imaging) that subclinical coronary artery disease after stroke may be more common than expected. As noted by Dr. Sposato et al., the cohort reported by Sioka may have been selected for patients at risk of more coronary artery disease, given the stroke mechanisms and vascular profile of the included patients. Whatever the mechanism of myocardial injury, clinicians ought to monitor closely for concomitant cardiac disease among patients with recent cerebral infarction.

In their prospective, randomized, single-blind phase II clinical trial of patients with Parkinson Disease (PD), Dr. Hacker et al. had previously shown that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can slow progression of tremor and reduce the dopaminergic treatment requirement in patients with early PD. In their 5-year follow-up study published in Neurology , the investigators report the safety and tolerability of this neurosurgical intervention. Importantly, there were numerically similar adverse events with DBS as with best medical therapy (66 vs 68), with 5 events being procedural complications (2 neurocognitive complications and 1 case each of postprocedural hematoma, surgical scar, and pneumocephalus). Compared with medical therapy, STN DBS reduced the long-term severity of dyskinesias and dopamine treatment requirement and was associated with clinically significant improvements in several standardized Parkinson Disease metrics. Although these results are encouraging, independent comments by Drs. Fasano and Bhowmick and by Dr. Sidiropoulos would caution the interpretation that STN DBS may reduce the risk of disease progression. The authors acknowledge the limitations of this phase II study and are optimistic that the ongoing phase III randomized clinical trial will put this question to rest. In their prospective, randomized, single-blind phase II clinical trial of patients with Parkinson Disease (PD), Dr. Hacker et al. had previously shown that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can slow progression of tremor and reduce the dopaminergic treatment requirement in patients with early PD. In their 5-year follow-up study published in Neurology , the investigators report the safety and tolerability of this neurosurgical intervention. Importantly, there were numerically similar adverse events with DBS as with best medical therapy (66 vs 68), with 5 events being procedural complications (2 neurocognitive complications and 1 case each of postprocedural hematoma, surgical scar, and pneumocephalus). Compared with medical therapy, STN DBS reduced the long-term severity of dyskinesias and dopamine treatment requirement and was associated with clinically significant improvements in several standardized Parkinson Disease metrics. Although these results are encouraging, independent comments by Drs. Fasano and Bhowmick and by Dr. Sidiropoulos would caution the interpretation that STN DBS may reduce the risk of disease progression. The authors acknowledge the limitations of this phase II study and are optimistic that the ongoing phase III randomized clinical trial will put this question to rest.

Neuroprognostication after cardiac arrest often remains reliant on neurophysiologic and serologic testing. To better prognosticate outcomes among patients with early epileptiform activity on EEG, Dr. Barbella et al. modeled various EEG predictors of favorable outcome using updated neurophysiologic criteria. Early absence of epileptiform activity, continuous background amplitude with reactivity, and later stimulus-induced rhythmic periodic or ictal discharges (SIRPIDs) strongly predicted favorable long-term outcomes in these patients after cardiac arrest (area under the curve 0.96, 95% CI 0.91–1.00). In a reader response, Dr. Sethi highlights that SIRPIDs may indicate brain reactivity, but they are not associated with cerebral hyperperfusion (as in the case of seizures). Both the investigators and Dr. Sethi agree that later SIRPIDs need not be treated aggressively in these patients. This study adds considerably to the neuroprognostication literature by showing early epileptiform activity may not always be a poor prognostic marker after cardiac arrest. Even in the presence of epileptiform activity, some features indicate a reasonable probability of functional recovery. As the investigators note in their methods—intensive care withdrawal was considered in patients with treatment-resistant myoclonus or status epilepticus, absent somatosensory-evoked potentials, incomplete return of brainstem reflexes, and elevated neuron specific enolase levels. Unsurprisingly, each of these findings strongly predicted poor outcomes. Therefore, the high sensitivity and specificity of the NEC2RAS score for predicting poor outcome does not disentangle it from the possibility of it contributing to the self-fulfilling prophecy. Neuroprognostication after cardiac arrest often remains reliant on neurophysiologic and serologic testing. To better prognosticate outcomes among patients with early epileptiform activity on EEG, Dr. Barbella et al. modeled various EEG predictors of favorable outcome using updated neurophysiologic criteria. Early absence of epileptiform activity, continuous background amplitude with reactivity, and later stimulus-induced rhythmic periodic or ictal discharges (SIRPIDs) strongly predicted favorable long-term outcomes in these patients after cardiac arrest (area under the curve 0.96, 95% CI 0.91–1.00). In a reader response, Dr. Sethi highlights that SIRPIDs may indicate brain reactivity, but they are not associated with cerebral hyperperfusion (as in the case of seizures). Both the investigators and Dr. Sethi agree that later SIRPIDs need not be treated aggressively in these patients. This study adds considerably to the neuroprognostication literature by showing early epileptiform activity may not always be a poor prognostic marker after cardiac arrest. Even in the presence of epileptiform activity, some features indicate a reasonable probability of functional recovery. As the investigators note in their methods—intensive care withdrawal was considered in patients with treatment-resistant myoclonus or status epilepticus, absent somatosensory-evoked potentials, incomplete return of brainstem reflexes, and elevated neuron specific enolase levels. Unsurprisingly, each of these findings strongly predicted poor outcomes. Therefore, the high sensitivity and specificity of the NEC2RAS score for predicting poor outcome does not disentangle it from the possibility of it contributing to the self-fulfilling prophecy.

BackgroundUnprecedented workflow shifts during the coronavirus disease 2019 (COVID-19) pandemic have contributed to delays in acute care delivery, but whether it adversely affected endovascular thrombectomy metrics in acute large vessel occlusion (LVO) is unknown.MethodsWe performed a retrospective review of observational data from 14 comprehensive stroke centers in nine US states with acute LVO. EVT metrics were compared between March to July 2019 against March to July 2020 (primary analysis), and between state-specific pre-peak and peak COVID-19 months (secondary analysis), with multivariable adjustment.ResultsOf the 1364 patients included in the primary analysis (51% female, median NIHSS 14 [IQR 7–21], and 74% of whom underwent EVT), there was no difference in the primary outcome of door-to-puncture (DTP) time between the 2019 control period and the COVID-19 period (median 71 vs 67 min, P=0.10). After adjustment for variables associated with faster DTP, and clustering by site, there remained a trend toward shorter DTP during the pandemic (βadj=-73.2, 95% CI −153.8–7.4, Pp=0.07). There was no difference in DTP times according to local COVID-19 peaks vs pre-peak months in unadjusted or adjusted multivariable regression (βadj=-3.85, 95% CI −36.9–29.2, P=0.80). In this final multivariable model (secondary analysis), faster DTP times were significantly associated with transfer from an outside institution (βadj=-46.44, 95% CI −62.8 to – -30.0, Padj=-2.15, 95% CI −4.2to – -0.1, P=0.05).ConclusionsIn this multi-center study, there was no delay in EVT among patients treated for intracranial occlusion during the COVID-19 era compared with the pre-COVID era.

To date, intravenous alteplase remains the only FDA-approved pharmacologic agent for the treatment of acute ischemic stroke. Among the contraindications to systemic thrombolysis with alteplase is therapeutic anticoagulation (or the use of warfarin with an INR >1.7), but not combination antiplatelet therapy. The most feared complication of treatment, symptomatic intracranial hemorrhage (sICH), may be more common in patients on dual antiplatelet pretreatment (DAPP) as shown in several studies and one previous meta-analysis. However, these data have not been consistently replicated. In their updated meta-analysis of 9 studies, including one randomized controlled clinical trial, 2 prospective registries, and 6 retrospective registries, Dr. Malhotra et al. observed that DAPP was associated with a two-fold higher odds of sICH in unadjusted regression (OR 2.26, 95% CI 1.39–3.67). This negative effect remained despite the use of varying definitions of sICH (SITS-MOST, ECASS II, and National Institute of Neurological Disorders and Stroke). However, after adjustment for confounders, the relationship no longer achieved statistical significance (ORadj 2.03, 95% CI 0.75–5.52, p = 0.16). Drs. Xu and Hu believed the analysis may have been confounded by overlapping patients between some of the included studies in this meta-analysis. Drs. Katsanos and Tsivgoulis confirmed—and we have independently verified—that there are no overlapping patients in this meta-analysis. Furthermore, the authors report the prospective TRISP registry corroborate the lack of a statistically significant, independent relationship between DAPP and sICH after thrombolysis (ORadj 1.29, 95% CI 0.82–2.05, p = 0.27). Although this information may provide us with greater reassurance regarding the safety of intravenous alteplase in patients on DAPP, these data highlight the importance of a priori significance thresholds. We believe readers should not be discouraged from using this FDA-approved acute treatment in patients prescribed DAPP but that does not mean one should not be cautious with it. To date, intravenous alteplase remains the only FDA-approved pharmacologic agent for the treatment of acute ischemic stroke. Among the contraindications to systemic thrombolysis with alteplase is therapeutic anticoagulation (or the use of warfarin with an INR >1.7), but not combination antiplatelet therapy. The most feared complication of treatment, symptomatic intracranial hemorrhage (sICH), may be more common in patients on dual antiplatelet pretreatment (DAPP) as shown in several studies and one previous meta-analysis. However, these data have not been consistently replicated. In their updated meta-analysis of 9 studies, including one randomized controlled clinical trial, 2 prospective registries, and 6 retrospective registries, Dr. Malhotra et al. observed that DAPP was associated with a two-fold higher odds of sICH in unadjusted regression (OR 2.26, 95% CI 1.39–3.67). This negative effect remained despite the use of varying definitions of sICH (SITS-MOST, ECASS II, and National Institute of Neurological Disorders and Stroke). However, after adjustment for confounders, the relationship no longer achieved statistical significance (ORadj 2.03, 95% CI 0.75–5.52, p = 0.16). Drs. Xu and Hu believed the analysis may have been confounded by overlapping patients between some of the included studies in this meta-analysis. Drs. Katsanos and Tsivgoulis confirmed—and we have independently verified—that there are no overlapping patients in this meta-analysis. Furthermore, the authors report the prospective TRISP registry corroborate the lack of a statistically significant, independent relationship between DAPP and sICH after thrombolysis (ORadj 1.29, 95% CI 0.82–2.05, p = 0.27). Although this information may provide us with greater reassurance regarding the safety of intravenous alteplase in patients on DAPP, these data highlight the importance of a priori significance thresholds. We believe readers should not be discouraged from using this FDA-approved acute treatment in patients prescribed DAPP but that does not mean one should not be cautious with it.

Using their pooled, prospective multicenter registry of over 11,000 Korean stroke survivors, Dr. Kim et al. reported the estimated direct healthcare costs in the years after acute ischemic stroke. Unsurprisingly, the estimated direct costs of care (including costs of inpatient and outpatient visits, prescription medications, and long-term care) were significantly greater in the year after stroke than the year before (mean $38,152 USD vs $8,718 USD), with a 5-year cumulative poststroke cost estimated at $117,576 USD. Importantly, there was considerable variation in the 5-year cumulative healthcare costs based on 3-month disability using the modified Rankin Scale (mRS). Compared with patients with no disability (mRS 0), patients dependent on others for ambulation and for activities of daily living (mRS 4) incurred considerably greater costs over the same period ($279,188 vs $53,578). Because healthcare administrators and policy makers determine healthcare reimbursement rates for various conditions and treatments, it is critical that any independent benefit of acute stroke intervention (e.g., reperfusion therapies) be evaluated thoroughly—as pointed out by Drs. Ganesh and Varma. In this analysis, recanalization therapies were strongly associated with better 3-month functional outcomes but paradoxically increased inpatient and outpatient care costs in the final multivariable model. It seems that the long-term functional disability (3-month mRS) was the principal driver of the cost effect, and after adjustment for this variable, any cost savings from recanalization could be negated. To clarify whether (and to what degree) acute recanalization therapies may mediate the long-term cost savings in stroke survivors, the investigators are exploring ways to model this in a follow-up analysis. Using their pooled, prospective multicenter registry of over 11,000 Korean stroke survivors, Dr. Kim et al. reported the estimated direct healthcare costs in the years after acute ischemic stroke. Unsurprisingly, the estimated direct costs of care (including costs of inpatient and outpatient visits, prescription medications, and long-term care) were significantly greater in the year after stroke than the year before (mean $38,152 USD vs $8,718 USD), with a 5-year cumulative poststroke cost estimated at $117,576 USD. Importantly, there was considerable variation in the 5-year cumulative healthcare costs based on 3-month disability using the modified Rankin Scale (mRS). Compared with patients with no disability (mRS 0), patients dependent on others for ambulation and for activities of daily living (mRS 4) incurred considerably greater costs over the same period ($279,188 vs $53,578). Because healthcare administrators and policy makers determine healthcare reimbursement rates for various conditions and treatments, it is critical that any independent benefit of acute stroke intervention (e.g., reperfusion therapies) be evaluated thoroughly—as pointed out by Drs. Ganesh and Varma. In this analysis, recanalization therapies were strongly associated with better 3-month functional outcomes but paradoxically increased inpatient and outpatient care costs in the final multivariable model. It seems that the long-term functional disability (3-month mRS) was the principal driver of the cost effect, and after adjustment for this variable, any cost savings from recanalization could be negated. To clarify whether (and to what degree) acute recanalization therapies may mediate the long-term cost savings in stroke survivors, the investigators are exploring ways to model this in a follow-up analysis.

It is clear that the care of children with neurologic disease is often complex, requiring substantial effort on the part of the provider and multidisciplinary team, and considerable time allocated to training future pediatric neurologists. According to recently published data from the Child Neurology Society (CNS) Task Force, burnout was reported in a significant number of faculty in all but 1 of 25 surveyed programs. Furthermore, the burnout seems to be related—at least in part—to unreachable work Relative Value Units (wRVUs) established by administrative staff. In this review, Dr. Zupanc and colleagues recount their experience with the CNS Task Force survey and report how heavily wRVUs are weighted when it comes to physician compensation and expectations. The authors argue that reliance on wRVUs as the sole measure of academic productivity is inherently flawed. Emphasis was placed on marrying the mission of hospital programs with expectations and compensation of child neurologists. If community outreach, education of future child neurologists, and clinical research are among the core responsibilities of faculty, it is self-evident that sufficient time and resources be dedicated to these pursuits. Dr. Wollack agrees that wRVU targets create hardships for child neurologists, who are often requested to generate far more wRVUs when compared with other pediatric subspecialty providers. Dr. Nash and colleagues underscore the importance of novel approaches to care delivery, such as a dedicated hospitalist model, which may alleviate some of the stresses created by the current wRVU system. As the number of child neurology providers dwindles, it is important now more than ever to rekindle institutional efforts to preserve this medical discipline. It is clear that the care of children with neurologic disease is often complex, requiring substantial effort on the part of the provider and multidisciplinary team, and considerable time allocated to training future pediatric neurologists. According to recently published data from the Child Neurology Society (CNS) Task Force, burnout was reported in a significant number of faculty in all but 1 of 25 surveyed programs. Furthermore, the burnout seems to be related—at least in part—to unreachable work Relative Value Units (wRVUs) established by administrative staff. In this review, Dr. Zupanc and colleagues recount their experience with the CNS Task Force survey and report how heavily wRVUs are weighted when it comes to physician compensation and expectations. The authors argue that reliance on wRVUs as the sole measure of academic productivity is inherently flawed. Emphasis was placed on marrying the mission of hospital programs with expectations and compensation of child neurologists. If community outreach, education of future child neurologists, and clinical research are among the core responsibilities of faculty, it is self-evident that sufficient time and resources be dedicated to these pursuits. Dr. Wollack agrees that wRVU targets create hardships for child neurologists, who are often requested to generate far more wRVUs when compared with other pediatric subspecialty providers. Dr. Nash and colleagues underscore the importance of novel approaches to care delivery, such as a dedicated hospitalist model, which may alleviate some of the stresses created by the current wRVU system. As the number of child neurology providers dwindles, it is important now more than ever to rekindle institutional efforts to preserve this medical discipline.

INTRODUCTION Although intravenous tissue plasminogen activator (IV tPA) is associated with neurologic deterioration (ND) caused by hemorrhage, whether it attenuates deterioration as a result of other etiologies including progressive stroke remains unexplored. The objective of this study was to determine whether IV tPA is associated with a reduced risk of ND caused by progressive stroke. METHODS A retrospective investigation of consecutively admitted patients with acute ischemic stroke (July 2008-June 2014) within 4.5 hours of symptom onset was conducted at a tertiary care center. Patients treated with IV tPA were compared with those who were not. The primary outcome was ND resulting from progressive infarction (a two-point increase in the National Institutes of Health Stroke Scale score during a 24-hour period). RESULTS A total of 699 registry patients (median age 65 years, interquartile range 55-76, 48.4% women, 70.4% nonwhite) were included in the study, and 58.1% received IV tPA. In crude regression, IV tPA did not reduce the odds of ND caused by progressive infarction; however, IV tPA-treated patients were at a 55% lower odds of ND from any cause (odds ratio 0.45, 95% confidence interval 0.32-0.61, P < 0.001). After adjusting for covariates, IV tPA use remained strongly associated with a 39% lower odds of ND from any cause (odds ratio 0.61, 95% confidence interval 0.48-0.79, P < 0.001). CONCLUSIONS Although IV tPA did not correlate with a reduced odds of progressive infarction, it was significantly associated with a lower odds of ND by any mechanism.

Elevated red blood cell distribution width (RDW) has been associated with thrombotic disorders including myocardial infarction, venous thromboembolism, and ischemic stroke, independent of other inflammatory and coagulation biomarkers. The purpose of this study was to determine whether elevated RDW is associated with cerebral infarction and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). In this retrospective single-center cohort of aSAH patients (October 2009–September 2014), elevated RDW was defined as a mean RDW >14.5 % during the first 14 days after aSAH. Outcomes included cerebral infarction (CI) by any mechanism and poor functional outcome, defined as discharge modified Rankin Scale (mRS) >4, indicating severe disability or death. Of 179 patients, 27 % had a high Hunt–Hess grade (IV–V), and 76 % were women. Twenty-four patients (13.4 %) underwent red blood cell (RBC) transfusion and compared to patients with normal RDW, patients with an elevated RDW were at greater odds of RBC transfusion (OR 2.56 [95 % CI, 1.07–6.11], p = 0.035). In univariate analysis, more patients with elevated RDW experienced CI (30.8 vs. 13.7 %, p = 0.017). In the multivariable model, elevated RDW was significantly associated with CI (OR 3.08 [95 % CI, 1.30–7.32], p = 0.011), independent of known confounders including but not limited to age, sex, race, high Hunt–Hess grade, and RBC transfusion. In multivariable analysis, RDW elevation was also associated with poor functional outcome (mRS > 4) at discharge (OR 2.59 [95 % CI, 1.04–629], p = 0.040). RDW elevation is associated with cerebral infarction and poor outcome after aSAH. Further evaluation of this association is warranted as it may shed light on mechanistic relations between anemia, inflammation, and thrombosis after aSAH.

Background.Transesophageal echocardiogram (TEE) is superior to transthoracic echocardiogram (TTE) in detecting left atrial thrombus (LAT), a risk factor for stroke, but is costly and invasive, carrying a higher risk for complications.Aims.To determine the utility of using left atrial enlargement (LAE) on TTE to predict LAT on TEE.Methods.AIS patients who presented in06/2008–7/2013and underwent both TTE and TEE were identified from our prospective stroke registry. Analysis consisted of multivariate logistic regression with propensity score adjustment and receiver operating characteristic (ROC) area under the curve (AUC) analyses.Results.219 AIS patients underwent both TTE and TEE. LAE on TTE was detected in 113 (51.6%) of AIS patients. Patients with LAE on TTE had higher proportion of LAT on TEE (8.4% versus 1.0%,p=0.018). LAE on TTE predicted increased odds of LAT on TEE (OR=8.83, 95% CI 1.04–74.83,p=0.046). The sensitivity and specificity for LAT on TEE by LAE on TEE were 88.89% and 52.20%, respectively (AUC=0.7054, 95% CI 0.5906–0.8202).Conclusions.LAE on TTE can predict LAT detected on TEE in nearly 90% of patients. This demonstrates the utility of LAE on TTE as a potential screening tool for LAT, potentially limiting unneeded costs and complications associated with TEE.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from infection of oligodendrocytes in the central nervous system with John Cunningham virus. Although PML is commonly diagnosed in immunocompromised patients with human immunodeficiency virus, it can also arise in other immunodeficient states. In this report, we present an unusual case of PML occurring 40years after chemoradiation therapy for Hodgkin lymphoma in a patient with normal total lymphocyte counts on annual surveillance. Although current guidelines recommend annual complete blood counts for patients in remission, this testing may be insufficient to monitor patients with chronic CD4+ lymphopenia.

There is not enough time in the day for neurology trainees to read as much as they are expected to read. But how often are trainees afforded the opportunity to flip through the pages of a journal article? Residents and fellows are on the move, so they need an educational medium that moves with them.

In their systematic review and meta-analysis of magnetic resonance spectroscopy (MRS) findings associated with hepatic encephalopathy (HE) due to cirrhosis, Zeng et al. observed a statistically significant increase in glutamine/glutamate metabolites with a decrease in myo-inositol and choline concentrations throughout the parietal, occipital, and basal ganglia regions among patients with HE vs those without HE. Of these metabolites, glutamine/glutamate presence in the parietal lobe was the most robust predictor of HE. In response to these findings, Dr. Gupta expresses concern as to the utility of advanced MRS imaging, given that HE remains a clinical diagnosis. The authors respond that MRS may be useful for earlier identification of mild or subclinical HE, which may lead to earlier, targeted treatment in patients at risk for later decompensation. In their systematic review and meta-analysis of magnetic resonance spectroscopy (MRS) findings associated with hepatic encephalopathy (HE) due to cirrhosis, Zeng et al. observed a statistically significant increase in glutamine/glutamate metabolites with a decrease in myo-inositol and choline concentrations throughout the parietal, occipital, and basal ganglia regions among patients with HE vs those without HE. Of these metabolites, glutamine/glutamate presence in the parietal lobe was the most robust predictor of HE. In response to these findings, Dr. Gupta expresses concern as to the utility of advanced MRS imaging, given that HE remains a clinical diagnosis. The authors respond that MRS may be useful for earlier identification of mild or subclinical HE, which may lead to earlier, targeted treatment in patients at risk for later decompensation.

Using pooled patient-level data from 5 randomized clinical trials, Dr. Carcel et al. evaluated sex disparities in the management and outcomes of patients with acute ischemic or hemorrhagic stroke. Compared with men, women were more frequently treated with antihypertensives and admitted to an acute stroke unit but were otherwise less frequently given acute antithrombotics, antipyretics (when fever was present), glucose- or lipid-lowering agents, or treated in an intensive care unit. With the exception of an antipyretic for fever, it is unclear whether these disparities in treatment reflect missed opportunities in care or suggest sex differences in the presence (or severity) of preexisting comorbidities. Incompletely characterized is the disparity in treatment with glycemic agents, which could be confounded by severity of hyperglycemia during hospitalization, whereas the differential use of antithrombotics could be confounded by the inclusion of both ischemic and hemorrhagic stroke trials. Compared with men in this cohort, women were more likely to survive stroke at 3 months, albeit with greater disability than male survivors. This disability difference likely has several explanations, as Drs. Ganesh and Varma indicate in their response to the article, with the big confounder being survival bias. Furthermore, the disparate premorbid disability between sexes before stroke could have contributed to the higher mortality rate seen in men, as pointed out by Drs. Ganesh and Varma. A more detailed analysis on the impact of premorbid disability is presently under review and will illustrate what sex differences in outcome exist—if any—when patients are stratified by premorbid disability. Using pooled patient-level data from 5 randomized clinical trials, Dr. Carcel et al. evaluated sex disparities in the management and outcomes of patients with acute ischemic or hemorrhagic stroke. Compared with men, women were more frequently treated with antihypertensives and admitted to an acute stroke unit but were otherwise less frequently given acute antithrombotics, antipyretics (when fever was present), glucose- or lipid-lowering agents, or treated in an intensive care unit. With the exception of an antipyretic for fever, it is unclear whether these disparities in treatment reflect missed opportunities in care or suggest sex differences in the presence (or severity) of preexisting comorbidities. Incompletely characterized is the disparity in treatment with glycemic agents, which could be confounded by severity of hyperglycemia during hospitalization, whereas the differential use of antithrombotics could be confounded by the inclusion of both ischemic and hemorrhagic stroke trials. Compared with men in this cohort, women were more likely to survive stroke at 3 months, albeit with greater disability than male survivors. This disability difference likely has several explanations, as Drs. Ganesh and Varma indicate in their response to the article, with the big confounder being survival bias. Furthermore, the disparate premorbid disability between sexes before stroke could have contributed to the higher mortality rate seen in men, as pointed out by Drs. Ganesh and Varma. A more detailed analysis on the impact of premorbid disability is presently under review and will illustrate what sex differences in outcome exist—if any—when patients are stratified by premorbid disability.

In their recent meta-analysis of 4 randomized-controlled trials (RCTs) evaluating the safety and efficacy of IV alteplase for patients treated beyond 4.5 hours after last known well, Dr. Tsivgoulis et al. confirm each trial's reported advantage of treatment over placebo. Although the risk-to-benefit ratio of IV alteplase undoubtedly dwindles with time—as prior trials and meta-analyses have demonstrated—there is a population of slow—or perhaps, slower—progressors who may yet benefit from treatment in the extended treatment window. Important to note is the 4 included RCTs from this meta-analysis restricted patient inclusion based on the presence of a reversible ischemic lesion, as identified via perfusion CT or diffusion-weighted MRI. Among patients who meet these imaging and other clinical criteria, the risk of symptomatic hemorrhage following thrombolysis is considerable (adjusted odds ratio 6.22, 95% confidence interval 1.37–28.26), and yet the long-term outcomes demonstrate a clear functional benefit without a higher probability of mortality. In response, Dr. Ishida cautions readers that these data do not indicate a shift in the paradigm of acute treatment for all-comers. Instead, they should be used to extend treatment opportunities for historically ineligible patients. What's more is that we should not use these data to justify treatment delays or to curtail stroke education emphasizing rapid evaluation and triage for stroke-like symptoms. Time is still tissue, although it may be more or less tissue on the individual patient level. In their recent meta-analysis of 4 randomized-controlled trials (RCTs) evaluating the safety and efficacy of IV alteplase for patients treated beyond 4.5 hours after last known well, Dr. Tsivgoulis et al. confirm each trial's reported advantage of treatment over placebo. Although the risk-to-benefit ratio of IV alteplase undoubtedly dwindles with time—as prior trials and meta-analyses have demonstrated—there is a population of slow—or perhaps, slower—progressors who may yet benefit from treatment in the extended treatment window. Important to note is the 4 included RCTs from this meta-analysis restricted patient inclusion based on the presence of a reversible ischemic lesion, as identified via perfusion CT or diffusion-weighted MRI. Among patients who meet these imaging and other clinical criteria, the risk of symptomatic hemorrhage following thrombolysis is considerable (adjusted odds ratio 6.22, 95% confidence interval 1.37–28.26), and yet the long-term outcomes demonstrate a clear functional benefit without a higher probability of mortality. In response, Dr. Ishida cautions readers that these data do not indicate a shift in the paradigm of acute treatment for all-comers. Instead, they should be used to extend treatment opportunities for historically ineligible patients. What's more is that we should not use these data to justify treatment delays or to curtail stroke education emphasizing rapid evaluation and triage for stroke-like symptoms. Time is still tissue, although it may be more or less tissue on the individual patient level.

High-convexity tight sulci (HCTS) has emerged in the last decade as a radiographic biomarker among cognitively impaired individuals with enlarged subarachnoid spaces, with most of the literature reporting an association with normal pressure hydrocephalus (NPH) and responsiveness to CSF shunting. Using their previously validated, automated imaging analysis of HCTS—which was further validated by a neuroradiologist in this investigation—Drs. Graff-Radford and colleagues explored the relationships between HCTS and various cognitive and radiographic parameters in a cohort of 684 patients aged ≥50 years. Patients with HCTS had more frequent cognitive impairment, subcortical microvascular ischemic disease with lower white matter and cortical volumes, and (most importantly) lower Tau burden. The investigators reported that the lower Tau burden in patients with HCTS indicated that subarachnoid space enlargement could not be related to Alzheimer pathology. Furthermore, the fact that HCTS correlated strongly with less cortical volume (which might otherwise suggest an underlying tauopathy) suggests that this imaging signature could be used to identify a subgroup of cognitively impaired patients without Alzheimer pathology and who may not respond to targeted Alzheimer therapeutics. Drs. Alali and Laticevschi recall their related observations from the Geneva NPH cohort, which further validate HCTS as a radiographic indicator of a nontauopathy condition. Together, these studies typify biomarkers like HCTS as indicators of a nontauopathy state, which could be useful in future clinical trials enrolling patients with neurodegenerative conditions. High-convexity tight sulci (HCTS) has emerged in the last decade as a radiographic biomarker among cognitively impaired individuals with enlarged subarachnoid spaces, with most of the literature reporting an association with normal pressure hydrocephalus (NPH) and responsiveness to CSF shunting. Using their previously validated, automated imaging analysis of HCTS—which was further validated by a neuroradiologist in this investigation—Drs. Graff-Radford and colleagues explored the relationships between HCTS and various cognitive and radiographic parameters in a cohort of 684 patients aged ≥50 years. Patients with HCTS had more frequent cognitive impairment, subcortical microvascular ischemic disease with lower white matter and cortical volumes, and (most importantly) lower Tau burden. The investigators reported that the lower Tau burden in patients with HCTS indicated that subarachnoid space enlargement could not be related to Alzheimer pathology. Furthermore, the fact that HCTS correlated strongly with less cortical volume (which might otherwise suggest an underlying tauopathy) suggests that this imaging signature could be used to identify a subgroup of cognitively impaired patients without Alzheimer pathology and who may not respond to targeted Alzheimer therapeutics. Drs. Alali and Laticevschi recall their related observations from the Geneva NPH cohort, which further validate HCTS as a radiographic indicator of a nontauopathy condition. Together, these studies typify biomarkers like HCTS as indicators of a nontauopathy state, which could be useful in future clinical trials enrolling patients with neurodegenerative conditions.

In their longitudinal survey of more than 8,000 patients with episodic migraine and selected comorbidities, Drs. Lipton et al. reported the results of the CaMEO Study. The investigators used 3 unique mathematical models to estimate the effect of various comorbidities on the progression of episodic migraine to chronic migraine. All comorbidity classes independently contributed to disease progression, and the effect was cumulative—with more comorbidities conferring a greater risk than fewer comorbidities. Dr. Gupta expresses concerns regarding the usefulness of classifying migraine subtypes, as there is presently unclear biologic heterogeneity of various migraine phenotypes. In response, the authors emphasize the importance of distinguishing unique migraine syndromes, as they may signify distinct biomarkers of disease or demonstrate a differential responsiveness to certain therapeutics. The authors acknowledge that the results of this study are one of several steps, which may lead to the improved care of patients with migraine. In their longitudinal survey of more than 8,000 patients with episodic migraine and selected comorbidities, Drs. Lipton et al. reported the results of the CaMEO Study. The investigators used 3 unique mathematical models to estimate the effect of various comorbidities on the progression of episodic migraine to chronic migraine. All comorbidity classes independently contributed to disease progression, and the effect was cumulative—with more comorbidities conferring a greater risk than fewer comorbidities. Dr. Gupta expresses concerns regarding the usefulness of classifying migraine subtypes, as there is presently unclear biologic heterogeneity of various migraine phenotypes. In response, the authors emphasize the importance of distinguishing unique migraine syndromes, as they may signify distinct biomarkers of disease or demonstrate a differential responsiveness to certain therapeutics. The authors acknowledge that the results of this study are one of several steps, which may lead to the improved care of patients with migraine.

Using the 2013 Nationwide Readmissions Database, which contains patient-level data for nearly half of Americans who were hospitalized for medical illness during that year, Drs. Stein and colleagues examined the length of stay and other outcomes among patients who were readmitted within 30 days of an index stroke event. Although the reported reasons for readmission to a different hospital vs the initial hospital were similar, patients readmitted to a different hospital were more likely to have longer hospitalizations, to incur higher hospitalization costs, and to be more likely to die during readmission. Drs. Chen and colleagues highlighted how social factors—such as dissatisfaction with care at the initial hospital—and index stroke severity or care could have influenced these outcome measures. Although stroke severity and subjective patient satisfaction are data elements that were not specifically captured in this national readmissions database, the authors adjusted for clinical severity using All Patient Refined Diagnosis Related Groups' severity of illness, and they adjusted for each patient's risk of mortality using a standardized score in their final multivariable model. Furthermore, patients were excluded from the analysis if they had been transferred from the index institution to a higher level of care to reduce confounding by unsatisfactory treatment. The effect of prolonged hospitalization with higher costs and a higher mortality rate persists in patients who are readmitted after an acute stroke. Factors that predict readmission need to be carefully considered before initial discharge. Using the 2013 Nationwide Readmissions Database, which contains patient-level data for nearly half of Americans who were hospitalized for medical illness during that year, Drs. Stein and colleagues examined the length of stay and other outcomes among patients who were readmitted within 30 days of an index stroke event. Although the reported reasons for readmission to a different hospital vs the initial hospital were similar, patients readmitted to a different hospital were more likely to have longer hospitalizations, to incur higher hospitalization costs, and to be more likely to die during readmission. Drs. Chen and colleagues highlighted how social factors—such as dissatisfaction with care at the initial hospital—and index stroke severity or care could have influenced these outcome measures. Although stroke severity and subjective patient satisfaction are data elements that were not specifically captured in this national readmissions database, the authors adjusted for clinical severity using All Patient Refined Diagnosis Related Groups' severity of illness, and they adjusted for each patient's risk of mortality using a standardized score in their final multivariable model. Furthermore, patients were excluded from the analysis if they had been transferred from the index institution to a higher level of care to reduce confounding by unsatisfactory treatment. The effect of prolonged hospitalization with higher costs and a higher mortality rate persists in patients who are readmitted after an acute stroke. Factors that predict readmission need to be carefully considered before initial discharge.

In spite of the considerable benefits to interventions for modifiable vascular disease risk factors, evidence indicates most ischemic strokes continue to be associated with poorly controlled lifestyle behaviors and medical conditions. In their nested cohort study of the Post-Stroke Disease Management STROKE-CARD trial, Drs. Boehme et al. found that 4 out of 5 patients with ischemic stroke had at least 1 inadequately managed lifestyle behavior or vascular comorbidity. Surprisingly, patients who had a prior stroke were even more likely to have 1 inadequately managed risk factor—which the authors attribute to the more extensive recommendations for secondary stroke prevention (e.g., antithrombotic and statin use) when compared to primary prevention. While the study highlights the failure of primary prevention strategies across stroke patients, it was limited in that only 8 risk factors were assessed. As Dr. Kelly indicates, chronic kidney disease (CKD) is one important vascular risk factor that was not addressed in this study. While CKD may not necessarily be a modifiable risk factor (in the sense that hypertension and body mass index may be modifiable), the presence of CKD may be a limiting factor for certain pharmacologic interventions for primary or secondary prevention. Using an admission glomerular filtration rate (GFR) cutoff of

In their prospective, observational cohort of 150 patients with clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS), Drs. Pfuhl et al. found that intrathecal IgM levels were significantly and independently predictive of conversion from CIS to RRMS. In a multivariable Cox regression, the presence of intrathecal IgM antibodies even outperformed oligoclonal bands and intrathecal IgG antibodies as a predictor for later RRMS. Drs. Alcala et al. recount their previously published, similar findings. They also suggest that the presence of intrathecal IgM levels could guide the decision to treat with disease-modifying therapies. That said, fewer than one-quarter of all patients in this cohort with CIS or RRMS harbored intrathecal IgM antibodies. As Pfuhl et al. emphasized, the proximate reason for intrathecal IgM antibodies and clinical course of patients with and without such antibodies needs further exploration. Although there is much we still do not fully understand, all investigators recommend leveraging these and other biomarkers of disease activity to individualize care for patients with multiple sclerosis. In their prospective, observational cohort of 150 patients with clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS), Drs. Pfuhl et al. found that intrathecal IgM levels were significantly and independently predictive of conversion from CIS to RRMS. In a multivariable Cox regression, the presence of intrathecal IgM antibodies even outperformed oligoclonal bands and intrathecal IgG antibodies as a predictor for later RRMS. Drs. Alcala et al. recount their previously published, similar findings. They also suggest that the presence of intrathecal IgM levels could guide the decision to treat with disease-modifying therapies. That said, fewer than one-quarter of all patients in this cohort with CIS or RRMS harbored intrathecal IgM antibodies. As Pfuhl et al. emphasized, the proximate reason for intrathecal IgM antibodies and clinical course of patients with and without such antibodies needs further exploration. Although there is much we still do not fully understand, all investigators recommend leveraging these and other biomarkers of disease activity to individualize care for patients with multiple sclerosis.