Rates of Adverse Events and Outcomes among Stroke Patients Admitted to Primary Stroke Centers.

BACKGROUND AND PURPOSE: To identify the beneficial effects of primary stroke centers (PSCs) certification by Joint Commission (JC), we compared the rates of in-hospital adverse events and discharge outcomes among ischemic stroke patients admitted to PSCs and those admitted to non-PSC hospitals in the United States. METHODS: We obtained the data from the Nationwide Inpatient Sample from 2010 and 2011. The analysis was limited to states that publicly reported hospital identity. PSCs were identified by matching the Nationwide Inpatient Sample hospital files with the list provided by JC. The analysis was limited to patients (age ≥18 years) discharged with a principal diagnosis of ischemic stroke (International Classification of Disease, 9th Revision, codes 433.x1, 434.x1). RESULTS: We identified a total of 123,131 ischemic stroke patients from 28 states. A total of 72,982 (59.3%) patients were admitted to PSCs. After adjusting for age, gender, race or ethnicity, comorbidities, All Patients Refined Diagnosis Related Groups (APR-DRG)-based disease severity, and hospital teaching status, patients admitted to PSCs were at lower risk of in-hospital adverse events complications: pneumonia (odds ratio [OR], .8; 95% confidence interval [CI], .7-.8) and sepsis (OR, .7; 95% CI, .6-.8). Patients admitted to PSCs were more likely to receive thrombolysis (OR, 1.6; 95% CI, 1.5-1.7). The mean cost of hospitalization (95% CI) of the patients was significantly higher in patients admitted at PSCs compared with those admitted at non PSC hospitals $47621 (47099-48144) vs. $35229 (34803-35654), P < .0001). The patients admitted to PSCs had lower inpatient mortality (OR, .8; 95% CI, .8-.9) and were more likely to be discharged with none to minimal disability (OR, 1.1; 95% CI, 1.0-1.1). CONCLUSIONS: Compared with non-PSC admissions, patients admitted to PSCs are less likely to experience hospital adverse events and more likely to experience better discharge outcomes.

Neuroprotective effect of asiatic acid in rat model of focal embolic stroke.

Asiatic acid (AA) is a pleiotropic neuroprotective agent that has been shown to attenuate infarct volume in mouse and rat models of focal ischemia and has a long clinically relevant therapeutic time-window. Because in a future trial AA would be administered with tissue-plasminogen activator (t-PA), the only approved acute stroke therapy, we sought to determine the effect of AA when co-administered with t-PA in a rat focal embolic stroke model. Male rats were treated with AA (75 mg/kg) alone, low-dose t-PA (2.5 mg/kg) alone, or a combination of AA and low-dose t-PA at 3 h after inducing embolic stroke. AA significantly reduced infarct volume whereas low-dose t-PA alone did not reduce infarct volume compared with vehicle. Significantly, combination treatment further enhanced reduction of infarct volume versus AA alone. Treatment with AA reduced cytochrome c (CytoC) and apoptosis-inducing factor (AIF) release from brain mitochondria after ischemia. AA was also neuroprotective against L-glutamate-induced toxicity in primary cortical neurons. In summary, combination treatment with AA and low-dose t-PA at 3 h after embolic stroke reduces infarct volume, improves neurological outcome, and provides neuroprotection. The neuroprotective effects of AA were partially associated with reduction of AIF and CytoC release.

Lymphocyte cell kinase activation mediates neuroprotection during ischemic preconditioning.

The molecular mechanisms underlying preconditioning (PC), a powerful endogenous neuroprotective phenomenon, remain to be fully elucidated. Once identified, these endogenous mechanisms could be manipulated for therapeutic gain. We investigated whether lymphocyte cell kinase (Lck), a member of the Src kinases family, mediates PC. We used both in vitro primary cortical neurons and in vivo mouse cerebral focal ischemia models of preconditioning, cellular injury, and neuroprotection. Genetically engineered mice deficient in Lck, gene silencing using siRNA, and pharmacological approaches were used. Cortical neurons preconditioned with sublethal exposure to NMDA or oxygen glucose deprivation (OGD) exhibited enhanced Lck kinase activity, and were resistant to injury on subsequent exposure to lethal levels of NMDA or OGD. Lck gene silencing using siRNA abolished tolerance against both stimuli. Lck-/- mice or neurons isolated from Lck-/- mice did not exhibit PC-induced tolerance. An Lck antagonist administered to wild-type mice significantly attenuated the neuroprotective effect of PC in the mouse focal ischemia model. Using pharmacological and gene silencing strategies, we also showed that PKCε is an upstream regulator of Lck, and Fyn is a downstream target of Lck. We have discovered that Lck plays an essential role in PC in both cellular and animal models of stroke. Our data also show that the PKCε-Lck-Fyn axis is a key mediator of PC. These findings provide new opportunities for stroke therapy development.

Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.

BACKGROUND AND PURPOSE: Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose-response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. METHODS: Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose-response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. RESULTS: The pharmacokinetic studies showed that AA (75 mg/kg) has a half-life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration was at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. CONCLUSIONS: Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window, and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy.

Wallenberg's syndrome with extradural-extracranial origin of the posterior inferior cerebellar artery.

We report a case of lateral medullary syndrome (LMS) with extradural origin of the posterior inferior cerebellar artery (PICA). A 45-year-old construction worker presented with acute signs and symptoms of typical LMS. Prolonged work-related neck extension was reported just prior to the onset of symptoms. Cerebral angiography revealed a patent vertebrobasilar tree with an extradural origin of an otherwise normal appearing PICA ipsilaterally. Workup did not show evidence for cardioembolic or atheroembolic source. The presence of an extradural origin of PICA may be considered a predisposing factor for non-traumatic LMS associated with head and neck movement.

Peripheral neuropathy: differential diagnosis and management.

Peripheral neuropathy has a variety of systemic, metabolic, and toxic causes. The most common treatable causes include diabetes mellitus, hypothyroidism, and nutritional deficiencies. The diagnosis requires careful clinical assessment, judicious laboratory testing, and electrodiagnostic studies or nerve biopsy if the diagnosis remains unclear. A systematic approach begins with localization of the lesion to the peripheral nerves, identification of the underlying etiology, and exclusion of potentially treatable causes. Initial blood tests should include a complete blood count, comprehensive metabolic profile, and measurement of erythrocyte sedimentation rate and fasting blood glucose, vitamin B12, and thyroid-stimulating hormone levels; specialized tests should be ordered if clinically indicated. Lumbar puncture and cerebrospinal fluid analysis may be helpful in the diagnosis of Guillain-Barré syndrome and chronic inflammatory demyelinating neuropathy. Electrodiagnostic studies, including nerve conduction studies and electromyography, can help in the differentiation of axonal versus demyelinating or mixed neuropathy. Treatment should address the underlying disease process, correct any nutritional deficiencies, and provide symptomatic treatment.

Cardiac dysfunction after left permanent cerebral focal ischemia: the brain and heart connection.

BACKGROUND AND PURPOSE: Stroke can lead to cerebrogenic cardiac arrhythmias. We sought to investigate the effect of ischemic stroke on cardiac function in a mouse model of permanent middle cerebral artery occlusion (pMCAO). METHODS: Twenty-four hours after the induction of focal ischemia, cardiac function was measured in mice by endovascular catheterization of the heart. Immediately after hemodynamic measurements, mice were euthanized and brains were excised and sectioned to measure infarct volume and the severity of insular cortex injury. Myocardial damage was evaluated by hematoxylin-eosin staining. Serum and heart levels of norepinephrine (NE) were also determined. RESULTS: Cardiac dysfunction occurred in 9 out of 14 mice that underwent left pMCAO. In these 9 mice, the severity of left insular cortex lesion was greater than the mice with normal heart function. The serum and heart levels of NE were significantly higher in left pMCAO mice with heart dysfunction. Liner regression analysis indicates significant inverse correlation between the severity of left insular cortex damage and heart dysfunction. Mice that underwent right pMCAO did not exhibit cardiac dysfunction. CONCLUSIONS: This study shows that left focal cerebral ischemia can produce cardiac dysfunction, which is associated with the extent of left insular cortex damage. Furthermore, mice exhibiting cardiac dysfunction had elevated levels of NE in the serum and heart.

Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia.

Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or beta-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood-brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood-brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.

Extent of intra-arterial calcification on head CT is predictive of the degree of intracranial atherosclerosis on digital subtraction angiography.

BACKGROUND: Intracranial intra-arterial calcifications (ICAC) are a common finding on head CT examinations, but their significance is not known. The aim of this study is to determine if a relationship exists between ICAC on head CT and the presence of a high-grade atherosclerotic stenosis on cerebral angiography. METHODS: This was a retrospective study of 108 consecutive patients admitted to the stroke service at Parkland Hospital in Dallas, Tex., USA. Each patient had undergone a head CT and catheter-based angiographic study to meet the inclusion criteria. Demographic information was recorded along with CT imaging data in regards to the amount of calcification. Angiographic images were reviewed independently, and a comparison was made to determine if calcification was predictive of finding a high-grade stenosis on angiography. RESULTS: A total of 108 consecutive patients with a mean age of 56 +/- 12 years were studied. Of the 540 vessels studied, 65 (12%) were found to have a stenosis of >or=50% on angiography, and 71 (13.1%) were found to have a calcium grade of 3 or 4 on head CT. ICAC appeared to be more common in the anterior circulation compared to the posterior circulation. Patients with grade 3 or 4 calcification of an intracranial vessel on head CT were more likely to have a stenosis of >or=50% on cerebral angiography. CONCLUSIONS: The presence of ICAC on head CT appears to correlate with the presence of an underlying intracranial stenosis on angiography. Further study is required to validate these preliminary findings.

Resting brain glucose uptake in headache-free migraineurs.

BACKGROUND AND OBJECTIVE: To compare metabolism in the brains of migraineurs during headache-free periods with those obtained from healthy volunteers. METHODS: Eleven migraineurs (defined by the International Headache Society's criteria) presented during spontaneous headache-free intervals to undergo (18)FDG PET brain imaging of glucose metabolism. The control group consisted of 14 healthy volunteers. Comparison of images was done using Statistical Parametric Mapping to detect significant (P < .05) differences in brain glucose metabolism between the 2 groups. RESULTS: Two regions of significant increase in glucose uptake were identified in migraineurs relative to the control population. The 2 regions were mapped predominantly to the posterior white matter of the cerebrum and cerebellum. CONCLUSIONS: Our study demonstrates the presence of what may be a primary metabolic disturbance in the posterior white matter of the brain in migraineurs.

Chemotherapy-related posterior reversible leukoencephalopathy syndrome.

BACKGROUND: A 45-year-old woman with small-cell lung cancer presented to a hospital emergency department in an acute confusional state, with blurred vision and mild headache. Following progressively increasing lethargy, she subsequently became unresponsive to tactile and verbal stimuli. She had recently been started on chemotherapy with carboplatin and gemcitabine. INVESTIGATIONS: Physical examination, imaging studies including brain MRI, noncontrast brain CT scans and magnetic resonance angiography, continuous EEG monitoring, and cerebrospinal fluid analysis. DIAGNOSIS: Posterior reversible leukoencephalopathy syndrome (PRES) related to chemotherapy, and nonconvulsive status epilepticus related to PRES. MANAGEMENT: Withholding of chemotherapeutic agents, and antiseizure therapy for the status epilepticus.

Hereditary neuropathy with liability to pressure palsies and amyotrophic lateral sclerosis.

A 56-year-old male with recurrent painless focal neuropathies and a family history of peripheral neuropathy of unknown etiology presented with progressively worsening of impaired sensations and weakness in his lower extremities. His initial electrodiagnostic evaluation was suggestive of severe sensory and motor peripheral polyneuropathy. The genetic testing was performed for familial causes of peripheral neuropathy as there was a family history of peripheral neuropathy of unknown etiology. The patient was found to have 1.5-Mb deletion in the PMP22 gene which was confirmatory of hereditary neuropathy with liability to pressure palsies (HNPP). He developed progressive upper and lower extremity weakness, bulbar dysfunction and widespread fasciculations during the course of his illness. He was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). This is the second reported case of HNPP associated with ALS. We discuss significant clinical and electrodiagnostic findings of this interesting case.

Diffusion-weighted imaging: not all that glitters is gold.

Diffusion-weighted imaging (DWI) is a sophisticated magnetic resonance imaging (MRI) technique with rapid acquisition time and high sensitivity for depicting acute cerebral ischemia. It is currently part of the routine workup in most medical centers when ischemic stroke is in the differential diagnosis. DWI helps establish a diagnosis of acute ischemic infarct even in cases where the clinical presentation is not typical for ischemic stroke. However, contrary to popular belief, not every hyperintensity on DWI is an ischemic stroke. Consequently, DWI with high intensity signals, commonly called "positive" DWI, is sometimes misinterpreted and leads to incorrect medical management. In this report, we briefly discuss some of the essential, technical aspects of DWI and report various clinical scenarios, which may lead to "positive" DWI findings but are not ischemic strokes. Although the sensitivity of DWI for ischemic stroke is very high, the specificity is not as high, and a "positive" DWI does not exclude other diagnoses that should be considered based on each patient's clinical history and examination, and the appearance of other sequences of MRI scans.

Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia.

Carnosine (beta-alanyl-L-histidine) has been shown to exhibit neuroprotection in rodent models of cerebral ischemia. In the present study, we further characterized the effects of carnosine treatment in a mouse model of permanent focal cerebral ischemia and compared them with its related peptides anserine and N-acetylated carnosine. We also evaluated the efficacy of bestatin, a carnosinase inhibitor, in ameliorating ischemic brain damage. Permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery (pMCAO). Mice were subsequently randomly assigned to receive an intraperitoneal injection of vehicle (0.9% saline), carnosine, N-acetyl carnosine, anserine, bestatin alone, or bestatin with carnosine. Infarct size was examined using 2,3,5-triphenyltetrazolium chloride staining 1, 3, and 7 days following pMCAO, and neurological function was evaluated using an 18-point-based scale. Brain levels of carnosine were measured in treated mice using high-performance liquid chromatography 1 day following pMCAO. We demonstrated that treatment with carnosine, but not its analogues, was able to significantly reduce infarct volume and improve neurological function compared with those in vehicle-treated mice. These beneficial effects were maintained for 7 days post-pMCAO. In contrast, compared with the vehicle-treated group, bestatin-treated mice displayed an increase in the severity of ischemic lesion, which was prevented by the addition of carnosine. These new data further characterize the neuroprotective effects of carnosine and suggest that carnosine may be an attractive candidate for testing as a stroke therapy.

Therapeutic role of zonisamide in neuropsychiatric disorders.

Zonisamide (ZNS), a sulfonamide antiepileptic drug, is indicated as an adjunct therapy for partial seizure disorders with and without secondary generalization. ZNS has a favorable pharmacokinetic profile because of its rapid absorption and high bioavailability. Its activity is related to the blockade of voltage gated sodium and calcium channels, modulation of central dopaminergic, GABAergic, and serotonergic functions, as well as inhibition of carbonic anhydrase and monoamine oxidase B. ZNS has potential efficacy for an array of neuropsychiatric disorders including migraine and other headache syndromes, neuropathic pain, Parkinson's disease, essential tremor, stroke, obesity, anxiety, bipolar and binge-eating disorders.

The effect of anticonvulsant drugs on the fibrinolytic activity of tissue plasminogen activator.

BACKGROUND AND PURPOSE: Several anticonvulsant drugs have been found to be neuroprotective in preclinical models of stroke, and such drugs may possibly be given in combination with other stroke treatments such as recombinant tissue plasminogen activator (rt-PA). The goal of this study was to test for potential interactions between rt-PA and selected anticonvulsants. METHODS: A spectrophotomeric assay was used to monitor the lysis of fibrin clots in the presence of rt-PA and the drugs levetiracetam, valproic acid, phenytoin and phenobarbital. RESULTS: The drugs tested were found to have no effect on either the rate or total amount of lysis induced by rt-PA. CONCLUSIONS: Although further studies are required in order to explore the effects of these drugs in stroke patients, the results suggest that co-administration of rt-PA and anticonvulsant drugs may be safe and viable.

Periodic lateralized epileptiform discharges: an initial electrographic pattern in reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy (RPLE) is a unique clinicoradiological entity characterized by diverse neurological symptoms with bilateral posterior cerebral white matter edema. It is frequently associated with seizures but rarely with status epilepticus. Periodic lateralized epileptiform discharges (PLEDs) as an initial electrographic pattern in a patient with RPLE have never been reported. We discuss a 47-year-old woman with a newly diagnosed non-small cell carcinoma of the lung on etoposide who was admitted with encephalopathy. Initial EEG demonstrated PLEDs. She later developed nonconvulsive status epilepticus. Magnetic resonance imaging (MRI) revealed bilateral subcortical edema predominantly of the temporo-occipital lobes. Discontinuation of etoposide resulted in full clinical, electrical recovery within 10 days and significant radiological improvement within 15 days. Our case indicates the importance of identifying and addressing any modifiable etiologic factors of RPLE. We emphasize identification of the unique initial electrographic pattern of PLEDs, which may be a predisposing factor to status epilepticus or an indication of structural damage.

The clinical significance of EEG cyclic alternating pattern during coma.

To define the clinical significance of EEG "cyclic alternating pattern" (ECAP). ECAP is the periodic presence of a high-voltage slow waves alternating with low voltage irregular faster activity. This term was first described in comatose patients in 1944. It has been less recognized and may be underreported since then. The clinical significance of ECAP in the state of coma remains unknown. We reviewed our prospective EEG database for consecutive patients studied over a period of 4 years (n = 4,819) looking for patterns consistent with ECAP. We reviewed the charts of the patients with the above EEG pattern to define the clinical setting and the eventual outcome. Eleven patients were identified. All patients identified were found to be in the coma state at the time of the EEG. The majority of patients (n = 10) survived the coma, and half returned to the community in good functional status. ECAP is seen rarely in comatose patients. Regardless of the cause of the coma, the presence of ECAP carries an overall good prognosis for both survival and recovery.

Medicolegal considerations with intravenous tissue plasminogen activator in stroke: a systematic review.

Background. Intravenous tPA (tissue plasminogen activator) therapy remains underutilized in patients with Acute Ischemic Stroke (AIS). Anecdotal data indicates that physicians are increasingly liable for administering and for failure to administer tPA. Methods. An extensive search of Medline, Embase, Westlaw, LexisNexis Legal, and Google Scholar databases was performed. Case studies that involved malpractice litigation in ischemic stroke and thrombolytic therapy were analyzed systematically. Results. We identified 789 ischemic stroke litigation cases, of which 46 cases were related to intravenous tPA and stroke litigation. Case descriptions of 40 cases were available. Data for verdicts were available for 38 patients. The most frequent plaintiff claim was related to failure to administer intravenous tPA (38, 95%). Only 2 (5.0%) claim involved complications of treatment with tPA. Hospitals were defendants in majority of the 36 cases. Physicians were involved in 33 cases. While ED physicians were involved in 25 (60.52%) cases, neurologists were involved in 8 (20.0%) cases. There were 26 (65%) defendant-favored and 12 (30%) plaintiff-favored verdicts. Conclusion. Physicians and hospitals are at an increased risk of litigation in patients with AIS when in IV-tPA is being considered for treatment. While majority of the cases litigated were cases where tPA was not administered, only about 1 in 20 cases was litigated when complications occurred.

ABCD2 Score and Large-Artery Atherosclerosis.

BACKGROUND AND PURPOSE: Extracranial stenosis (ECS) or intracranial stenosis (ICS) are independent risk factors for stroke after transient ischemic attack (TIA). We examined the association of the age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score, a validated risk prediction model for stroke after TIA, and the presence of ICS or ECS. METHODS: Vascular imaging and ABCD2 scores were obtained in a retrospective cohort of 77 consecutive patients diagnosed with TIA in a single center emergency department. The association between vascular stenosis and ABCD2 scores and how each related to clinical outcome was examined. RESULTS: In all, 30 (39.2%) TIA patients had 37 stenotic lesions; 15 (40.5%) stenotic lesions were ICS and 22 (59.5%) stenotic lesions were ECS. A total of 7 patients (9.5%) had both ECS and ICS lesions. Patients with ABCD2 > 3 were more likely to have ICS (odds ratio [OR] = 6.25, confidence interval [CI] 1.39-32.44, P = .009) and ECS (OR = 5.25, CI = 1.56-17.66, P = .005). Of the 37 stenotic lesions, 21 (56.7%) were symptomatic; 4 (19.2%) of these had an ABCD2 ≤ 3. At 7 days, there were 4 ischemic strokes, 3 had previously demonstrated symptomatic stenotic lesions, and all had ABCD2 scores > 3. CONCLUSIONS: Compared to patients in the low-risk ABCD2 scores, the patients with medium- to high-risk ABCD2 scores are more likely to have symptomatic and asymptomatic vascular stenotic lesions. However, 1 in 5 patients with low-risk ABCD2 score has symptomatic stenotic lesions, indicating ABCD2 score does not identify all patients with symptomatic stenotic lesions.