Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Systemic lupus erythematosus presenting as Guillain-Barré syndrome.

A 37-year-old woman developed progressive symmetrical weakness with areflexia, consistent with Guillain-Barré syndrome. After initially briefly responding to intravenous immunoglobulin, her weakness progressed markedly. Further investigation identified a new diagnosis of systemic lupus erythematosus with lupus nephritis. Following additional plasma exchange and corticosteroids, the lupus activity remitted and she made a complete neurological recovery.

Contrast-induced encephalopathy: a complication of coronary angiography.

Contrast-induced encephalopathy is a rare idiosyncratic reaction to contrast material. A 56-year-old woman with hypertension developed a hemiparesis with confusion and disorientation 3 hours after routine coronary angiography. The procedure had been prolonged, and during it she had received 130 mL of iopromide contrast. A metabolic screen was negative, and cerebral angiography and MR scan of brain were normal. She recovered completely by day 5. Contrast-induced encephalopathy should be considered in patients developing focal neurological deficits following coronary angiography. Patients requiring investigations to exclude acute stroke in this setting should not receive additional intravenous or intra-arterial contrast, although MR with gadolinium appears safe. Better awareness of this complication should avoid potentially harmful interventions such as thrombolysis.

Contrast-induced encephalopathy following cardiac catheterization.

OBJECTIVES: To describe the epidemiology, pathophysiology, clinical presentation, and management of contrast-induced encephalopathy (CIE) following cardiac catheterization. BACKGROUND: CIE is an acute, reversible neurological disturbance directly attributable to the intra-arterial administration of iodinated contrast medium. METHODS: The PubMed database was searched and all cases in the literature were retrieved and reviewed. RESULTS: 52 reports of CIE following cardiac catheterization were found. Encephalopathy, motor and sensory disturbances, vision disturbance, opthalmoplegia, aphasia, and seizures have been reported. Transient cortical blindness is the most commonly reported neurological syndrome, occurring in approximately 50% of cases. The putative mechanism involves disruption of the blood brain barrier and direct neuronal injury. Contrast-induced transient vasoconstriction has also been implicated. Symptoms typically appear within minutes to hours of contrast administration and resolve entirely within 24-48 hr. Risk factors may include hypertension, diabetes mellitus, renal impairment, the administration of large volumes of iodinated contrast, percutaneous coronary intervention or selective angiography of internal mammary grafts, and previous adverse reaction to iodinated contrast. Characteristic findings on cerebral imaging include cortical and sub-cortical contrast enhancement on computed tomography (CT). Imaging findings in CIE may mimic subarachnoid hemorrhage or cerebral ischemia; the Hounsfield scale on CT and the apparent diffusion coefficient on magnetic resonance imaging (MRI) are useful imaging tools in distinguishing these entities. In some cases, brain imaging is normal. Prognosis is excellent with supportive management alone. CIE tends to recur, although re-challenge with iodinated contrast without adverse effects has been documented. CONCLUSIONS: CIE is an important clinical entity to consider in the differential diagnosis of stroke following cardiac catheterization. Given that prognosis is excellent with supportive management only, physicians should be aware of it, and consider it prior to initiating thrombolysis. © 2016 Wiley Periodicals, Inc.

Recurrent contrast-induced encephalopathy following coronary angiography.

Contrast-induced encephalopathy (CIE) is an acute and reversible neurological disturbance associated with the intra-arterial administration of iodinated contrast medium during cardiac catheterisation. It may manifest with encephalopathy, motor and sensory disturbances; vision disturbances, including cortical blindness, ophthalmoplegia, aphasia; and seizures. Disruption of the blood-brain barrier and direct neuronal toxicity are believed to be implicated in the pathophysiology of the syndrome. Symptoms appear soon after contrast administration and resolve completely within 24-48 h. Risk factors may include hypertension, diabetes mellitus, renal impairment, the administration of large volumes of iodinated contrast, percutaneous coronary intervention or selective angiography of internal mammary grafts and previous adverse reaction to iodinated contrast. On cerebral imaging, CIE may mimic subarachnoid haemorrhage or cerebral ischaemia, but imaging may be normal. Prognosis is excellent with supportive management alone. CIE may recur, but re-challenge with iodinated contrast without adverse effects has been documented. CIE is a diagnosis of exclusion and is an important clinical entity to consider in the differential diagnosis of stroke following cardiac catheterisation. Physicians should be aware of it and consider it prior to initiating thrombolysis.

Safety of intravenous thrombolysis for ischemic stroke in patients treated with warfarin.

OBJECTIVE: Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) ≤ 1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization, and long-term functional outcome in stroke thrombolysis remains unclear. METHODS: We analyzed data from 45,074 patients treated with IV tPA enrolled in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Register. A total of 768 patients had baseline warfarin treatment with INR ≤ 1.7. Outcome measures were SICH, arterial recanalization, mortality, and functional independence at 3 months. RESULTS: Patients on warfarin with INR ≤ 1.7 were older, had more comorbidities, and had more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio [aOR] = 1.23, 95% confidence interval [CI] = 0.72-2.11 per SITS-MOST; aOR = 1.26, 95% CI = 0.82-1.70 per European Cooperative Acute Stroke Study II) after adjustment for age, stroke severity, and comorbidities. Neither did warfarin independently influence mortality (aOR = 1.05, 95% CI = 0.83-1.35) or functional independence at 3 months (aOR = 1.01, 95% CI = 0.81-1.24). Arterial recanalization by computed tomography/magnetic resonance angiography trended higher in warfarin patients (62% [37 of 59] vs 55% [776/1,475], p = 0.066). Recanalization approximated by disappearance at 22 to 36 hours of a baseline hyperdense middle cerebral artery sign was increased (63% [124 of 196] vs 55% [3,901 of 7,099], p = 0.022). INTERPRETATION: Warfarin treatment with INR ≤ 1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with IV tPA for acute ischemic stroke.

Percutaneous left atrial appendage occlusion with a Watchman device following recurrent stroke on warfarin and rivaroxaban in patient with paroxysmal atrial fibrillation.

The optimal management of recurrent cardioembolic stroke in a patient on oral anticoagulation is controversial. Therapeutic strategies for secondary stroke prevention in such circumstances may include the intensification of oral anticoagulation, the addition of antiplatelet therapy to warfarin, or the use of a non-vitamin K antagonist instead of warfarin. However, there is no evidence to support these interventions, and indeed these strategies are not endorsed by the 2011 Guidelines on the Secondary Prevention of Stroke issued by the American Heart Association/American Stroke Association. Percutaneous occlusion of the left atrial appendage (LAA) has recently emerged as an acceptable non-pharmacological strategy to reduce the risk of cardioembolism in patients who cannot tolerate oral anticoagulation, but there is little evidence to support its use in the context of recurrent stroke despite oral anticoagulation. We present the case of a 66 year-old male with paroxysmal atrial fibrillation who experienced recurrent stroke despite treatment with warfarin initially, and rivaroxaban subsequently. After excluding non-cardioembolic causes of recurrent stroke, we proceeded with percutaneous occlusion of the LAA with a Watchman device. Nine months post-procedure he has not experienced recurrence of neurological symptoms. Our case provides anectodal evidence that catheter-based LAA occlusion can be beneficial in secondary stroke prevention where oral anticoagulation has been problematic.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy.

The widespread use of highly active antiretroviral therapy (HAART) in HIV-infected individuals mostly in developed countries has dramatically improved their prognosis. In such advantaged regions of the world, therefore, many patients are now transitioning from middle into older age, with altered patterns of disease. While previously a rare complication of HIV infection, cerebrovascular disease (particularly that associated with atherosclerosis) is becoming relatively more important in this treated group of individuals. This review summarises the evidence regarding the shifting epidemiology of cerebrovascular diseases affecting HIV-infected individuals. While outlining the association between HIV infection and AIDS and cerebrovascular disease, as well as opportunistic diseases and HIV-associated vasculopathies, the current evidence supporting an increase in atherosclerotic disease in treated HIV-infected individuals is emphasised and a management approach to ischaemic stroke in HIV-infected individuals is presented. Evidence supporting the important role of HAART and HIV infection itself in the pathogenesis of atherosclerotic disease is discussed, together with preventative approaches to this increasingly important disease process as the population ages. Finally, a discussion regarding the significant association between cerebrovascular disease and HIV-associated neurocognitive disorder is presented, together with possible mechanisms behind this relationship.

Neurocardiogenic pulmonary oedema: initial presentation of multiple sclerosis.

A previously healthy 20 year-old male presented with headache, acute pulmonary oedema and left ventricular dysfunction requiring intensive care admission. Cardiorespiratory symptoms resolved within three days; however, the patient complained of persistent headache and had gait unsteadiness. Magnetic resonance imaging showed a large demyelinating lesion in the caudal medulla with scattered cerebral plaques. The patient was subsequently diagnosed with multiple sclerosis. This case describes a rare initial presentation of multiple sclerosis with acute pulmonary oedema and cardiac dysfunction secondary to a lower brainstem lesion.

Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion: report from a randomized, controlled trial.

BACKGROUND AND PURPOSE: Central retinal artery occlusion is caused by a platelet-fibrin thrombus or embolic occlusion and is a stroke of the eye. Observational studies suggest that thrombolytics may restore ocular perfusion and visual function. We hypothesized that intravenous tissue-type plasminogen activator (tPA) administered within 24 hours of symptom onset might restore ocular perfusion and visual function. METHODS: A placebo-controlled, randomized trial of intravenous tPA versus intravenous saline was performed in patients with clinically defined central retinal artery occlusion within 24 hours of symptom onset. tPA was administered at a total dose of 0.9 mg/kg, with 10% given as a 1-minute bolus and the remainder over 1 hour. An improvement of visual acuity of 3 lines or more was considered significant. RESULTS: Twenty-five percent (2 of 8) of the tPA group experienced the primary outcome at 1 week after tPA versus none of the placebo group. One patient had an intracranial hemorrhage. The visual acuity improvement of these 2 patients was not sustained at 6 months. In both patients, tPA was administered within 6 hours of symptom onset. CONCLUSIONS: Although essentially a negative study, it does add to the evidence base of reperfusion in central retinal artery occlusion by showing that the time window for intervention is likely to be <6 hours. Reocclusion is a potential problem and may require adjuvant anticoagulation. Future studies should concentrate on determining the efficacy of thrombolytics in the <6-hour time window. Clinical Trial Registration- URL: http://www.anzctr.org.au. Unique identifier: 83102.

An unusual presentation of varicella zoster virus with acute cerebellitis and SIADH without a rash.

We report a case of varicella-zoster virus (VZV) infection with acute cerebellitis and encephalitis with associated Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in an elderly man presenting with acute cerebellar ataxia without antecedent rash. Cerebrospinal fluid examination (CSF) revealed a mononuclear pleocytosis, high protein, normal glucose, positive for VZV polymerase chain reaction (PCR). Early acyclovir treatment is beneficial for acute VZV cerebellitis. Clinicians should consider infectious Central Nervous System (CNS) causes for presentations of acute cerebellar ataxia in adult patients, particularly if there is an accompanying clouded sensorium.

Inflammation following stroke.

Stroke is one of the leading causes of mortality and morbidity. The stroke process triggers an inflammatory reaction that may last up to several months. Suppression of inflammation using a variety of drugs reduces infarct volume and improves clinical outcomes in animal models of stroke. This benefit occurs even with the initiation of therapy after 3 hours of onset of stroke, beyond the therapeutic window for thrombolysis with tPA. The use of neuroprotectants to suppress inflammation may widen the therapeutic time window for tPA while lessening its side-effects. Suppression of inflammation may also improve outcomes in animal models of haemorrhagic stroke. To date, clinical trials with anti-inflammatory agents in acute ischaemic stroke have failed to improve clinical outcomes. However, because of the potential for broader applicability across all aspects of stroke, a better understanding of anti-inflammatory mechanisms is important.

The existence and evolution of diffusion-perfusion mismatched tissue in white and gray matter after acute stroke.

BACKGROUND AND PURPOSE: Although white matter is a potential target of acute stroke therapy, there is uncertainty about its relative resistance to ischemia and whether it is capable of mounting a penumbral response. To explore these issues further, we examined the differential effects of ischemia on gray and white matter using magnetic resonance (MR) perfusion-diffusion mismatch after acute stroke. METHODS: MR imaging studies were performed within 12 hours in patients with initial hemispheric ischemic stroke. "At-risk" tissue was defined as tissue with abnormal diffusion-weighted imaging/perfusion-weight imaging or infarction on follow-up image. Tissue was segmented using a probabilistic atlas generated from age-matched controls. The proportions of "at-risk" tissue, which was penumbral at the time of imaging, were compared between gray and white matter. RESULTS: Thirty-two patients had diffusion-perfusion mismatched penumbral tissue present in both gray and white matter compartments. Although the absolute mismatch volumes were greater in gray (median 42 cm3, interquartile range 18 to 70 cm3) than in white matter (39 cm3, 17 to 49 cm3; P<0.001), the proportion of "at-risk" tissue, which was penumbral at the time of imaging (median 3.7 hours, range 1.5 to 9.9 hours) was greater in white (69%, 49% to 86%) than gray matter (62%, 52% to 75%; P=0.026). However, the proportions spontaneously salvaged by 3 months were similar in both compartments. CONCLUSIONS: These findings are consistent with white matter being able to mount an ischemic penumbral response in humans and being more resistant to cerebral ischemia than gray matter. They also raise the possibility that the therapeutic window is longer for white matter and may require alternative therapeutic strategies.

Is white matter involved in patients entered into typical trials of neuroprotection?

BACKGROUND AND PURPOSE: One of the reasons for the failure of trials of neuroprotection in stroke may be the lack of white matter (WM) protection. However, whether patients entered into typical neuroprotection trials have WM involved in the ischemic process is unknown. We studied patients who were enrolled in neuroprotection trials at our center and used a neuroimaging coregistration approach to determine whether final infarcts involved WM and, if so, in what proportion. We also aimed to provide the first in vivo volume distribution of gray matter (GM) and WM in normal stroke-aged brains. METHODS: Patients enrolled in trials of neuroprotection had late computed tomography or magnetic resonance scans coregistered in standard stereotaxic coordinate space after segmentation of symptomatic cerebral infarcts. These were then superimposed on a probabilistic map of GM and WM, which was developed from age-matched normal controls in whom GM and WM volumes were assessed. RESULTS: Forty-two patients (mean age, 73.7+/-10.5 years) were studied from 6 trials of neuroprotection. WM formed 41.7% of the brain volume in 37 control subjects (mean age, 73.5+/-8.4 years). In the segmented infarcts, WM comprised a median of 49% (interquartile range, 36.5 to 77.9) of the infarct volume. Ninety-five percent of infarcts had some involvement of WM tracts. CONCLUSIONS: WM occupies approximately 42% by volume of the normal stroke-aged brain. Patients entered into typical trials of neuroprotection may have significant WM volumes involved in the ischemic process, thus providing a rationale for the development of neuroprotectants for this compartment.

STroke imAging pRevention and treatment (START): A longitudinal stroke cohort study: Clinical trials protocol.

RATIONALE: Stroke and poststroke depression are common and have a profound and ongoing impact on an individual's quality of life. However, reliable biological correlates of poststroke depression and functional outcome have not been well established in humans. AIMS: Our aim is to identify biological factors, molecular and imaging, associated with poststroke depression and recovery that may be used to guide more targeted interventions. DESIGN: In a longitudinal cohort study of 200 stroke survivors, the START-STroke imAging pRevention and Treatment cohort, we will examine the relationship between gene expression, regulator proteins, depression, and functional outcome. Stroke survivors will be investigated at baseline, 24 h, three-days, three-months, and 12 months poststroke for blood-based biological associates and at days 3-7, three-months, and 12 months for depression and functional outcomes. A sub-group (n = 100), the PrePARE: Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke cohort, will also be investigated for functional and structural changes in putative depression-related brain networks and for additional cognition and activity participation outcomes. Stroke severity, diet, and lifestyle factors that may influence depression will be monitored. The impact of depression on stroke outcomes and participation in previous life activities will be quantified. STUDY OUTCOMES: Clinical significance lies in the identification of biological factors associated with functional outcome to guide prevention and inform personalized and targeted treatments. Evidence of associations between depression, gene expression and regulator proteins, functional and structural brain changes, lifestyle and functional outcome will provide new insights for mechanism-based models of poststroke depression.

Can the time window for administration of thrombolytics in stroke be increased?

Level 1 evidence now shows that thrombolysis in cases of acute ischaemic stroke is effective if administered within 3 hours of stroke onset. This benefit has been shown to be time dependent and potentially extends beyond 3 hours, with evidence that potentially viable penumbral tissue may be present in a significant proportion of cases well beyond 3-6 hours and, in isolated cases, perhaps up to 48 hours. This exposes a "stroke recovery gap", the difference observed between the clinical response to thrombolytic therapy in a given population of patients presenting with ischaemic stroke and the potential clinical recovery if all of the penumbra were salvaged under ideal circumstances. The means of bridging this "stroke recovery gap" using thrombolysis must involve extending the therapeutic time window (i.e. the time between stroke onset and administration of thrombolytics). Approaches to do this include the use of: (i) improved patient selection with modern neuroimaging techniques, particularly magnetic resonance imaging using perfusion-weighted image/diffusion-weighted image mismatch; (ii) newer thrombolytic agents; (iii) lower doses of these agents; (iv) varied methods of administration of thrombolytic therapy including combined intravenous and intra-arterial approaches; and (v) adjunctive therapies such as neuroprotectants. Should these means of extending the time window for thrombolysis prove successful, a more widespread use of this form of acute stroke therapy will be possible.