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The photophysics associated with the self-assembly of π-peptide molecules into 1-D nanostructures has been well-established, thus revealing the creation of nanoscale electronic conduits in aqueous media. Such materials have therapeutic potential in many biomedical applications. In this work, we report the in vivo deployment of these π-peptide nanostructures in brain tissue using photothrombotic stroke as a model application. A test peptide was used for brain injections, and the nanostructures formed were visualized with electron microscopy. A new peptide bearing a low-energy fluorescence dye was prepared to facilitate direct visualization of π-peptide localization in the brain cavity by way of fluorescence microscopy. This work demonstrates feasibility for in vivo application of π-peptide nanostructures toward pressing biomedical challenges.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing. Substantial advances are yet to be made in stroke rehabilitation practice to meet this demand and improve patient outcomes relative to current care. Several large intervention trials targeting motor recovery report that participants' motor performance improved, but to a similar extent for both the intervention and control groups in most trials. These neutral results might reflect an absence of additional benefit from the tested interventions or the many challenges of designing and doing large stroke rehabilitation trials. Strategies for improving trial quality include new approaches to the selection of patients, control interventions, and endpoint measures. Although stroke rehabilitation research strives for better trials, interventions, and outcomes, rehabilitation practices continue to help patients regain independence after stroke.

Introduction: The COVID-19 pandemic accelerated the adoption of telemedicine services for the delivery of outpatient neurological care. To date, teleneurology has been primarily used in the hospital setting related to both billing restrictions and the need for hands-on maneuvers to complete the neurological assessment. We sought to understand perceptions of neurology specialists during rapid proliferation of telemedicine services into their outpatient practices and the acceptance of this technology. Hypothesis: Neurologists may report profound challenges acclimating to the telemedicine platform, completing visits, and making clinical decisions via telemedicine. We also expected that neurology sub-specialties would differ in their attitudes. Methods: Adapted from the Telehealth Usability Questionnaire (TUQ), our 29 item questionnaire evaluated the teleneurology system in three domains: quality of the telemedicine platform, ability to conduct a sufficient neurological examination, and areas for improvement. The survey was distributed to 88 clinical Neurology faculty in the Johns Hopkins Health System. Seven-point Likert scale responses were collapsed into “Favorable”, “Neutral”, and “Unfavorable.” Within each domain, responses to individual questions were analyzed by neurology sub-specialty using descriptive statistics. Results: We received completed surveys from 46/88 (52%) neurology faculty. Of those, most reported comfort with the current platform (98%) and favorably regarded the system’s ease of use (73%) and quality (80%). However, responses indicated only average ability to troubleshoot telemedicine platform issues when they occurred (55%) and to complete a neurological exam (52%). Sub-specialty comparisons revealed differences in diagnostic confidence; only 30% of neuromuscular faculty indicated they could make accurate neurological diagnoses through a tele-exam as opposed to 84% or greater for other specialties. Conclusions: Teleneurology appears to be feasible and acceptable to a majority of academic neurologists, though diagnostic confidence may differ by sub-specialty. Improvements in technological infrastructure and care models are needed to advance telemedicine neurological care delivery.

Background Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. Methods Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. Results Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. Conclusions Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.

Little is known about the natural history of intracranial atherosclerotic plaque enhancement and its clinical implications. Our objective was to investigate the value of follow-up high-resolution contrast-enhanced vessel wall MRI (VWMRI) for classifying culprit plaques in patients with intracranial atherosclerotic disease (ICAD). Fourteen patients with symptomatic ICAD (50% females; median age 48 years) underwent serial 3T VWMRI. Fifty-five plaques were identified and graded based on the likelihood of having caused the ischemic event (non-culprit, indeterminate, culprit) and degree of enhancement (0, 1, 2) at baseline and follow-up (median follow-up, 140 days). For accuracy analysis, plaque enhancement at baseline and stable or increasing plaque enhancement at follow-up was tested to identify a culprit plaque, and areas under the receiver operating characteristic curves (AUCs) were compared. In 37/55 (67.3%) plaques, enhancement grade remained unchanged. Lack of enhancement was only seen in non-culprit plaques at baseline, and none developed enhancement over time. Enhancement never changed more than one grade. Thirty-seven percent (10/27) of non-culprit plaques that enhanced decreased in enhancement grade at follow-up, but no culprit plaques decreased in enhancement. AUC of baseline and follow-up plaque enhancement combined was significantly larger than AUC of baseline plaque enhancement alone to identify culprit plaques (0.733 vs. 0.567, p = 0.0001). Contrast enhancement of ICAD can persist months after the ischemic event. Lack of enhancement at baseline or a decrease in enhancement at follow-up suggests that the plaque is not culprit. Persistent enhancement from baseline to follow-up improves accuracy in identifying culprit plaques.

Background: The transition period from hospital to home is a highly vulnerable time for patients after stroke. COVID-19 restrictions have exacerbated safety concerns, stressed the health care system, and put patients at high risk after discharge. Here we describe pilot results from the Joint Stroke Transitional Technology-Enhanced Program (JSTTEP) designed to reduce post-stroke complications, avoid hospital readmission, and enhance recovery. Methods: JSTTEP is a novel, interprofessional program for patients discharged from the Johns Hopkins Comprehensive Stroke Center. In the first weeks after hospital discharge, stroke patients complete a series of multidisciplinary telemedicine visits to (1) reduce the risks of adverse events in the transition from hospital to home, and (2) develop a plan to facilitate a full recovery. The first joint visit is with stroke neurology and physical therapy for risk mitigation, and the second is with physiatry and occupational therapy for a recovery plan. Patients and caregivers participate in an interactive, online group education session covering topics about vascular risk factor modification, nutrition, exercise, fall prevention, and self-management skills. Results: In the first 4 months of the program, 50 patients were enrolled. Average age was 61 years; 26/50 (52%) were women, 23/50 (46%) were African American, and mean baseline NIHSS was 5.4. Of those 45/50 (90%) completed their visit, with 4/50 (8%) requiring conversion from video to phone visit. Unexpected 30-day hospital readmission rate was 3/50 (6%), one of whom was readmitted due to neurological issues identified during the JSTTEP appointment. Interpreter services were utilized for 5 completed video visits (Arabic, Mandarin, Spanish, Twi, Urdu). Patients reported the ability to include family members remotely in the visit as an advantage. Conclusions: The data demonstrate the feasibility and potential benefit of an interprofessional stroke telemedicine program designed to enhance post-stroke recovery. JSTTEP increased access to post-hospital care and reduced risks for adverse outcomes. The ongoing benefits and scaling of such a clinic will rely on permanent legislative and insurance changes to support such a care model.

BackgroundEvidence from animal studies suggests that greater reductions in post-stroke motor impairment can be attained with significantly higher doses and intensities of therapy focused on movement quality. These studies also indicate a dose-timing interaction, with more pronounced effects if high-intensity therapy is delivered in the acute/subacute, rather than chronic, post-stroke period.ObjectiveTo compare two approaches of delivering high-intensity, high-dose upper limb therapy in patients with subacute stroke: a novel exploratory neuro-animation therapy (NAT), and modified conventional occupational therapy (COT).MethodsTwenty-four patients were randomized to NAT or COT and underwent 30 sessions of 60 minutes time-on-task in addition to standard care. The primary outcome was the Fugl-Meyer Upper Extremity motor score (FM-UE). Secondary outcomes included: Action Research Arm Test (ARAT), grip strength, Stroke Impact Scale (SIS) hand domain, and upper-limb kinematics. Outcomes were assessed at baseline, and days 3, 90, and 180 post-training. Both groups were compared to a matched historical cohort (HC), which received only 30 minutes of upper limb therapy per day.ResultsThere were no significant between-group differences in FM-UE change or any of the secondary outcomes at any timepoint. Both high-dose groups showed greater recovery on the ARAT (7.3 ±2.9 pts, p=0.011), but not the FM-UE (1.4 ±2.6 pts, p =0.564) when compared to the HC.ConclusionsTwo forms of high-dose intensive upper limb therapy produced greater activity but not impairment improvements compared with regular care. Neuroanimation may offer a new enjoyable, efficient and scalable way to deliver increased upper limb therapy.Clinicaltrials.gov registration NCT02292251

Objective: Perinatal ischemic stroke is estimated to occur in 1/2300–1/5000 live births, but early differential diagnosis from global hypoxia-ischemia is often difficult. In this study, we tested the ability of a hand-held transcranial photoacoustic (PA) imaging probe to non-invasively detect a focal photothrombotic stroke (PTS) within 2 h of stroke onset in a gyrencephalic piglet brain. Approach: About 17 stroke lesions of approximately 1 cm2 area were introduced randomly in anterior or posterior cortex via the light/dye PTS technique in anesthetized neonatal piglets (n = 11). The contralateral non-ischemic region served as control tissue for discrimination contrast for the PA hemoglobin metrics: oxygen saturation, total hemoglobin (tHb), and individual quantities of oxygenated and deoxygenated hemoglobin (HbO2 and HbR). Main results: The PA-derived tissue oxygen saturation at 2 h yielded a significant separation between control and affected regions-of-interest (p < 0.0001), which were well matched with 24 h post-stroke cerebral infarction confirmed in the triphenyltetrazolium chloride-stained image. The quantity of HbO2 also displayed a significant contrast (p = 0.021), whereas tHb and HbR did not. The analysis on receiver operating characteristic curves and multivariate data analysis also agreed with the results above. Significance: This study shows that a hand-held transcranial PA neuroimaging device can detect a regional thrombotic stroke in the cerebral cortex of a neonatal piglet. In particular, we conclude that the oxygen saturation metric can be used alone to identify regional stroke lesions. The lack of change in tHb may be related to arbitrary hand-held imaging configuration and/or entrapment of red blood cells within the thrombotic stroke.

We describe a method to introduce naive mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.

Studies in humans and animal models show that most recovery from impairment occurs in the first 1–3 months after stroke as a result of both spontaneous recovery as well as increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived “sensitive period” of post-stroke plasticity defined by unique genetic, physiological, and structural events. Unfortunately, rehabilitative interventions in humans have not been able to exploit this sensitive period similar to that seen in animal models. Here, we review these data and suggest a path forward. Pre-clinical data reveal underlying mechanisms that define the post-stroke sensitive period. These data are then discussed in the context of the spontaneous post-stroke recovery described in humans. Future work will need to capitalize on unique interactions between the sensitive period, spontaneous recovery, and novel types of rehabilitative interventions.

Central nervous system vasculitides are elusive diseases that are challenging to diagnose because brain biopsies have high false-negative rates. We sought to test the ability of contrast-enhanced, high-resolution 3D vessel wall MR imaging to identify vascular inflammation and direct open biopsies of intracranial target vessels and adjacent brain parenchyma. Eight of 9 specimens revealed vascular inflammation. We conclude that vessel wall MR imaging can identify inflamed intracranial vessels, enabling precise localization of biopsy targets.

An 18-year-old woman with a history of vertigo and longstanding fluctuating hearing loss presented with increasing headaches, nausea, dizziness, confusion, and gait imbalance. She also experienced new onset rashes on her hands and intermittent episodes of eye pain. CSF analysis revealed lymphocytic

A 60-year-old woman with no known medical history presented with acute-onset altered mental status and aphasia. She was in her usual state of health until the time of presentation. She was found to have left middle and posterior cerebral artery (MCA and PCA) acute ischemic strokes and subsequently developed refractory status epilepticus. CT angiography showed moderate stenosis of the proximal left internal carotid artery (ICA), occlusion of the right ICA at its origin, and near-complete occlusion of the left vertebral artery (figure). Strokes were attributed to large-vessel atherosclerotic disease in the setting of multiple vascular risk factors including diabetes (A1c 13.5%), hypertension, and hyperlipidemia (low-density lipoprotein 244 mg/dL).

Background Up to 25% of acute stroke patients first note symptoms upon awakening. We hypothesized that patients awaking with stroke symptoms may be safely treated with intravenous alteplase (IV tPA) using non-contrast head CT (NCHCT), if they meet all other standard criteria. Methods The SAfety of Intravenous thromboLytics in stroke ON awakening (SAIL ON) was a prospective, open-label, single treatment arm, pilot safety trial of standard dose IV tPA in patients who presented with stroke symptoms within 0–4.5 hours of awakening. From January 30, 2013, to September 1, 2015, twenty consecutive wakeup stroke patients selected by NCHCT were enrolled. The primary outcome was symptomatic intracerebral hemorrhage (sICH) in the first 36 hours. Secondary outcomes included NIH stroke scale (NIHSS) at 24 hours; and modified Rankin Score (mRS), NIHSS, and Barthel index at 90 days. Results The average age was 65 years (range 47–83); 40% were women; 50% were African American. The average NIHSS was 6 (range 4–11). The average time from wake-up to IV tPA was 205 minutes (range 114–270). The average time from last known well to IV tPA was 580 minutes (range 353–876). The median mRS at 90 days was 1 (range 0–5). No patients had sICH; two of 20 (10%) had asymptomatic ICH on routine post IV tPA brain imaging. Conclusions Administration of IV tPA was feasible and may be safe in wakeup stroke patients presenting within 4.5 hours from awakening, screened with NCHCT. An adequately powered randomized clinical trial is needed. Clinical trial registration ClinicalTrials.gov NCT01643902.

Background and Purpose: Most functional upper extremity motor recovery occurs in the first 4 weeks after ischemic stroke in humans and in the first week in rodent models. The majority of functional recovery in humans is spontaneous (i.e. occurs as a result of endogenous repair processes rather than rehabilitative interventions). In mouse models of stroke, recovery is impaired when post-stroke rehabilitation is delayed and there is very little spontaneous recovery. Cerebrolysin is a polypeptide preparation shown to enhance neuronal plasticity and to promote motor recovery in patients after stroke. In mice, we tested the hypothesis that Cerebrolysin can act early after stroke to enhance spontaneous motor recovery. Methods: Adult C57Bl/6 mice were trained to perform a skilled prehension task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in the caudal forelimb area (rodent primary motor cortex). The mice were then randomized to receive Cerebrolysin or saline injections beginning 24-hours post-stroke. Both groups were then retrained at the same prehension task by a blinded investigator. Stroke volumes were compared using immunohistochemistry. Results: We have previously shown that training-associated recovery of prehension is complete if training is initiated after a 1-day delay but incomplete if training is initiated after a 7-day delay, even with additional training days. However, daily Cerebrolysin administration after stroke was associated with complete recovery of prehension by day 8, even in the absence of training. Stroke volumes were similar across all groups. Conclusions: We conclude that Cerebrolysin administration during an early time window can lead to spontaneous recovery of motor function without a protective effect on stroke volume. This is one of the first demonstrations of spontaneous motor recovery in a rodent stroke model. Our mouse model, with all of the attendant genetic benefits, should allow us to determine at the cellular and molecular level how endogenous plasticity and medications like Cerebrolysin interact to mediate recovery.

To characterize intracranial plaque inflammation in vivo by using three-dimensional (3D) high-spatial-resolution contrast material-enhanced black-blood (BB) magnetic resonance (MR) imaging and to investigate the relationship between intracranial plaque inflammation and cerebrovascular ischemic events.The study was approved by the institutional review board and was HIPAA compliant. Twenty-seven patients (19 men; mean age, 56.8 years ± 12.4 [standard deviation]) with cerebrovascular ischemic events (acute stroke, n = 20; subacute stroke, n = 2; chronic stroke, n = 3; transient ischemic attack, n = 2) underwent 3D time-of-flight MR angiography and contrast-enhanced BB 3-T MR imaging for intracranial atherosclerotic disease. Each identified plaque was classified as either culprit (the only or most stenotic lesion upstream from a stroke), probably culprit (not the most stenotic lesion upstream from a stroke), or nonculprit (not within the vascular territory of a stroke). Plaque contrast enhancement was categorized on BB MR images (grade 0, enhancement less than or equal to that of normal arterial walls seen elsewhere; grade 1, enhancement greater than grade 0 but less than that of the pituitary infundibulum; grade 2, enhancement greater than or equal to that of the pituitary infundibulum), and degree of contrast enhancement was calculated. Associations of the likelihood of being a culprit lesion with both plaque contrast enhancement and plaque thickness were estimated with ordinal logistic regression.Seventy-eight plaques were identified in 20 patients with acute stroke (21 [27%] culprit, 12 [15%] probably culprit, and 45 [58%] nonculprit plaques). In these patients, grade 2 contrast enhancement was associated with culprit plaques (odds ratio 34.6; 95% confidence interval: 4.5, 266.5 compared with grade 0) when adjusted for plaque thickness. Grade 0 was observed in only nonculprit plaques. Culprit plaques had a higher degree of contrast enhancement than did nonculprit plaques (25.9% ± 13.4 vs 13.6% ± 12.3, P = .003).Contrast enhancement of intracranial atherosclerotic plaque is associated with its likelihood to have caused a recent ischemic event and may serve as a marker of its stability, thereby providing important insight into stroke risk.

Background. Peripheral nerve injury leads to changes in neuronal activity in the contralateral and ipsilateral primary somatosensory cortices (S1), which may lead to enduring sensory dysfunction and pain. Plasticity in the barrel and visual cortices has been shown to occur in a layer-specific manner. However, little is known about the layer specific changes associated with limb injury. Objective. To determine the layer-specific changes in neuronal activity associated with short-term plasticity induced by peripheral nerve injury in the rat. Methods. In vivo electrophysiology recordings (multiunit activity and local field potential) and high-resolution functional magnetic resonance imaging techniques were applied to characterize neuronal and hemodynamic responses across the depth of S1 contralateral and ipsilateral to the injury. Results. Within 60 minutes following injury, atypical increases in neuronal and hemodynamic responses in the deprived S1, ipsilateral to the noninjured limb, were observed in response to stimulation of the noninjured limb. The most prominent increases in neuronal activity in the deprived S1 occurred in layer V. Conclusion. Layer V neurons provide the major output of S1 and they send and receive transcallosal input. Thus, the immediate changes in neuronal firing patterns in layer V induced by the injury, can adversely affect the activity of subcortical regions and also interfere with normal cortical processing and interhemispheric communication. Therefore, a rehabilitation strategy that targets layer V neurons activity and starts immediately after the injury may benefit the functional outcome.

Background and objective. Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity—a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Methods. Mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Results. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. Conclusions. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

Background and Purpose— Preliminary studies suggest that intracranial arteries are capable of accommodating plaque formation by remodeling. We sought to study the ability and extent of intracranial arteries to remodel using 3-dimensional high-resolution black blood magnetic resonance imaging and investigate its relation to ischemic events. Methods— Forty-two patients with cerebrovascular ischemic events underwent 3-dimensional time-of-flight magnetic resonance angiography and contrast-enhanced black blood magnetic resonance imaging examinations at 3 T for intracranial atherosclerotic disease. Each plaque was classified by location (eg, posterior versus anterior circulation) and its likelihood to have caused a stroke identified on magnetic resonance imaging (culprit, indeterminate, or nonculprit). Lumen area, outer wall area, and wall area were measured at the lesion and reference sites. Plaque burden was calculated as wall area divided by outer wall area. The arterial remodeling ratio (RR) was calculated as outer wall area at the lesion site divided by outer wall area at the reference site after adjusting for vessel tapering. Arterial remodeling was categorized as positive if RR>1.05, intermediate if 0.95≤RR≤1.05, and negative if RR Results— One hundred and thirty-seven plaques were identified in 42 patients (37% [50] posterior and 63% [87] anterior). Compared with anterior circulation plaques, posterior circulation plaques had a larger plaque burden (77.7±15.7 versus 69.0±14.0; P =0.008), higher RR (1.14±0.38 versus 0.95±0.32; P =0.002), and more often exhibited positive remodeling (54.0% versus29.9%; P =0.011). Positive remodeling was marginally associated with downstream stroke presence when adjusted for plaque burden (odds ratio 1.34, 95% confidence interval: 0.99–1.81). Conclusions— Intracranial arteries remodel in response to plaque formation, and posterior circulation arteries have a greater capacity for positive remodeling and, consequently, may more likely elude angiographic detection. Arterial remodeling may provide insight into stroke risk.

INTRODUCTION: Primary central nervous system vasculitis (PCNSV) is a rare inflammatory arteriopathy confined to the brain, spinal cord, and leptomeninges. Because of its nonspecific presentation and difficulties in making a positive diagnosis, empiric treatment is often instituted. CASE SERIES: We report a case series of 5 patients who were admitted or transferred to the Johns Hopkins Hospital with a clinical history and magnetic resonance imaging findings suggestive of PCNSV. Four patients had received at least 1 course of immunosuppression with high-dose intravenous (IV) corticosteroids and/or a corticosteroid-sparing agent. Each underwent an extensive workup including 4-vessel cerebral angiography and, in the majority of cases, brain biopsy to evaluate for mimics of PCNSV. In each of the 5 cases, an alternative diagnosis was found. CONCLUSIONS: We propose a cautious, multistep approach to the diagnosis of PCNSV, which takes into account more common diagnoses and avoids the pitfalls of empiric treatment.

Pathologic studies suggest that neovascularization and hemorrhage are important features of plaque vulnerability for disruption. Our aim was to determine the associations of these features in carotid plaques with previous cerebrovascular ischemic events by using high-resolution CE-MRI.Forty-seven patients (36 men; mean age 72.5 ± 10 years) underwent CE-MRI and MRA examinations for carotid plaque at 3T. IPH presence was recorded. Neovascularity was categorized by the degree of adventitial enhancement (0, absent; 1,50%; 2, ≥50%). Reader variability was assessed by using weighted κ. Associations with events were determined by using multivariable logistic regression.Intra- and inter-reader agreement for grading adventitial enhancement were good to excellent. IPH was present in 49% of patients and was associated with events (P = .03). Patients grouped by categories 0, 1, and 2 adventitial enhancement had increasing frequencies of events (14% category 0, 48% category 1, 65% category 2; P = .02). Events were associated with IPH (OR, 10.18; 95% CI, 1.42-72.21) and adventitial enhancement (compared with category 0: OR, 14.90, 95% CI, 0.98-225.93 for category 1; OR, 51.17, 95% CI, 3.4-469.8 for category 2) after controlling for age, sex, cardiovascular risk factors, wall thickness, and stenosis. Stenosis was not associated with events.Adventitial enhancement and IPH are independently associated with previous events and may provide important insight into stroke risk not achievable by stenosis.

Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) are a recently described form of epileptiform periodic discharges evoked by arousal. Similar to other periodic discharges (e.g., pseudoperiodic lateralized epileptiform discharges, generalized periodic epileptiform discharges, bilaterally independent epileptiform discharges), SIRPIDs lie somewhere along an ictal-interictal continuum. To determine whether SIRPIDs represent an ictal phenomenon reflected by increased focal cerebral perfusion on single-photon emission computerized tomography, or conversely an interictal pattern, the authors tested a patient with nonconvulsive status confirmed on EEG, which evolved to SIRPIDs with a concomittant contralateral hemiparesis. To test the ictal-increased flow hypothesis, a single-photon emission computerized tomography scan was obtained during a stimulus-induced train of rhythmic discharges on EEG, but it revealed no increase in tracer uptake. The authors conclude that SIRPIDs did not increase regional cerebral blood flow as would seizures. Thus, the evidence indicates little if any metabolic/blood flow activation with SIRPIDs, thus tempering the intensity with which SIRPIDs might be managed. This provides a testable paradigm for future patterns of uncertain epileptic significance.

The interrelationship between stroke and cancer is complex. Cancer and stroke may occur independently in a given patient, or cancer may directly or indirectly lead to stroke via: hypercoaguability, non-bacterial thrombotic endocarditis (NBTE), direct tumor compression of blood vessels, or treatment-related effects which potentiate stroke. Patients with cryptogenic stroke are relatively common, and under the right circumstances, may provide an opportunity to screen for occult malignancy. In this review, we discuss relevant data linking stroke and cancer as well as propose a testable algorithm for cancer screening in the patient with cryptogenic stroke. Future directions should focus on validating patient-care algorithms in prospective clinical trials to provide an evidence base for this important issue.

Background and Purpose— Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Methods— Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Results— Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. Conclusions— There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.

Brain-derived neurotrophic factor (BDNF) is thought to be involved in neuronal survival, migration, morphological and biochemical differentiation, and modulation of synaptic function in the CNS. In the rodent cortex, postnatal BDNF expression is initially low but subsequently increases to reach maximal levels around weaning. Thus, BDNF expression peaks at a time when both structural and functional maturation of cortical circuitry occurs. Although the function of BDNF has been probed using many approaches, its requirements during this phase of life have not previously been examined genetically. To test thein vivorequirements for BDNF during this important phase of development we generated early-onset forebrain-specificBDNFmutant mice. Although these mice undergo forebrain-restricted deletion ofBDNFby Cre-mediated recombination during embryogenesis, they are healthy, and we did not detect the loss of specific cortical excitatory or inhibitory neurons. However, the neocortex of 5-week-old mice was thinner, attributable at least partly to neuronal shrinkage. Importantly, although visual cortical layer 2/3 neurons in the mutants initially developed normal dendrite structure, dendritic retraction became apparent by 3 weeks of age. Thus, our observations suggest that cortically expressed BDNF functions to support the maintenance of cortical neuron size and dendrite structure rather than the initial development of these features. This is consistent with a role for BDNF in stabilizing the “survival” of circuitry during the phase of activity-dependent reorganization of cortical connectivity.

Loeys-Dietz syndrome is a recently described connective tissue disorder with a natural history of extreme vessel tortuosity and aggressive arterial aneurysm formation and rupture. This is the case of a 23-year-old woman with a large, dysplastic cavernous aneurysm who had successful endovascular treatment by flow diversion with the Pipeline embolisation device. Ten-month follow-up demonstrated complete aneurysm occlusion and curative reconstruction of the parent vessel without evidence of vessel injury or dissection. Endovascular treatment with flow-diverting devices is a valid treatment option and can be performed safely and effectively in this complex patient population.

3D-DSA is the 'gold standard' imaging technique for the diagnosis and characterization of intracranial aneurysms.To compare the image quality and accuracy of low dose 3D-DSA protocols in patients with unruptured intracranial aneurysms.The standard manufacturer 5 s 0.36 μGy/f protocol and one of three low dose 3D-DSA protocols (5 s 0.10 μGy/f, 5 s 0.17 μGy/f, 5 s 0.24 μGy/f) were performed in 12 patients with unruptured intracranial aneurysms. Three interventional neuroradiologists, two neurosurgeons, and two neurologists rated the image quality of all 3D reconstructions as good, acceptable, or poor. Three interventional neuroradiologists measured two dimensions of each aneurysm for all protocols. The radiation dose metric Ka,r (reference point air kerma, in mGy) was recorded for each 3D-DSA protocol.The standard 5 s 0.36 μGy/f protocol earned the highest average subjective rating of 2.76, followed by the 5 s 0.24 μGy/f (2.72), and 5 s 0.17 μGy/f (2.59) protocols. The ranges of differences in aneurysm measurements between the 5 s 0.24 μGy/f protocol and the standard were0.5 mm. The median Ka,r metrics for each protocol were as follows: 5 s 0.36 μGy/f (89.0 mGy), 5 s 0.24 μGy/f (57.7 mGy), 5 s 0.17 μGy/f (45.9 mGy), and 5 s 0.10 μGy/f (27.6 mGy).Low dose 3D-DSA protocols with preserved image quality are achievable, and can help reduce exposure of patients and operators to unnecessary radiation. The 5 s 0.24 μGy/f protocol generates one-third smaller radiation dose than the standard 5 s 0.36 μGy/f protocol without compromising diagnostic image quality or accuracy.

Recovery after stroke can occur either via reductions in impairment or through compensation. Studies in humans and nonhuman animal models show that most recovery from impairment occurs in the first 1-3 months after stroke as a result of both spontaneous reorganization and increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived sensitive period of postischemic plasticity defined by unique genetic, molecular, physiological, and structural events. In contrast, compensation can occur at any time after stroke. Here, we address both the biology of the brain's postischemic sensitive period and the difficult question of what kind of training (task-specific vs. a stimulating environment for self-initiated exploration of various natural behaviors) best exploits this period.Data suggest that three important variables determine the degree of motor recovery from impairment: the timing, intensity, and approach to training with respect to stroke onset; the unique postischemic plasticity milieu; and the extent of cortical reorganization.Future work will need to further characterize the unique interaction between types of training and postischemic plasticity, and find ways to augment and prolong the sensitive period using pharmacological agents or noninvasive brain stimulation.

SummaryPropofol is associated with abnormal motor events resembling seizures, the exact nature of these events remains to be elucidated. We describe here a case of seizure-like activity after propofol-induced conscious sedation accompanied by a prolactin rise, together suggesting that the event was ictal.

Adult neurogenesis occurs in two discrete neurogenic niches in the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampal formation. Under physiologic conditions, neurogenesis in these regions is thought to be important for the maintenance and reorganization of interneurons in the olfactory bulb (SVZ), and the modulation and refinement of existing circuits in the dentate gyrus (SGZ). In rodents, stroke enhances neurogenesis in these regions, and stroke-induced neurogenesis appears to play a role in functional recovery. However, little is known about the behavior of quiescent vs. activated pools of neural stem cells in response to stroke, or the mechanisms of stroke-induced neurogenesis at the cellular level. Here we tested the hypothesis that stroke-induced neurogenesis involves the activation of quiescent stem cell pools, either alone or in combination with further differentiation of activated precursors. We used a genetic labeling strategy for in vivo lineage tracing of quiescent, nestin-expressing radial glia-like (RGL) precursors in the SGZ to elucidate the effect of remote focal ischemic infarction on RGLs at a clonal level. Unilateral infarction of the visual cortex by photothrombosis in transgenic mice caused an increase in the number of differentiated neuronal precursors and a decrease in the number of quiescent RGLs in the ipsilateral SGZ. Furthermore, among activated RGL clones, there was an increase in symmetric and neurogenic RGL divisions in response to stroke, with a concomitant loss of astrogliogenic RGL divisions. These preliminary results suggest that stroke may alter hippocampal neurogenesis from a distance by activating quiescent RGL pools in the SGZ through an as-of-yet unidentified mechanism and pushing them toward a neuronal fate. In turn, this may accelerate the time-dependent depletion of this RGL population. We speculate that this phenomenon contributes to cognitive changes associated with stroke and may represent a target for pharmacological intervention.

Background and Purpose— Motor recovery after ischemic stroke in primary motor cortex is thought to occur in part through training-enhanced reorganization in undamaged premotor areas, enabled by reductions in cortical inhibition. Here we used a mouse model of focal cortical stroke and a double-lesion approach to test the idea that a medial premotor area (medial agranular cortex [AGm]) reorganizes to mediate recovery of prehension, and that this reorganization is associated with a reduction in inhibitory interneuron markers. Methods— C57Bl/6 mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke in the caudal forelimb area. The mice were then retrained and inhibitory interneuron immunofluorescence was assessed in prechosen, anatomically defined neocortical areas. Mice then underwent a second photocoagulation-induced stroke in AGm. Results— Focal caudal forelimb area stroke led to a decrement in skilled prehension. Training-associated recovery of prehension was associated with a reduction in parvalbumin, calretinin, and calbindin expression in AGm. Subsequent infarction of AGm led to reinstatement of the original deficit. Conclusions— We conclude that with training, AGm can reorganize after a focal motor stroke and serve as a new control area for prehension. Reduced inhibition may represent a marker for reorganization or it is necessary for reorganization to occur. Our mouse model, with all of the attendant genetic benefits, may allow us to determine at the cellular and molecular levels how behavioral training and endogenous plasticity interact to mediate recovery.

Steven R. Zeiler, Joseph Dedrick Jordan, Benjamin M. Greenberg, Peter W. Kaplan The Johns Hopkins Hospital, Department of Neurology, Pathology 627C 600 N. Wolfe Street, Baltimore, MD 21287 University of North Carolina, 919.966.5547 UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9003 The Johns Hopkins Bayview Medical Center, Department of Neurology, 4940 Eastern Avenue, Baltimore, MD 21224