Central Journal of Neurology & Translational Neuroscience Special Edition on Elisabeth B. Marsh* and Rafael H. Llinas Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Edited by: Elisabeth B. Marsh Rafael H. Llinas Department of Neurology Department of Neurology The Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine Baltimore, MD, USA Baltimore, MD, USA Introduction

e would like to thank the authors of the following papers for choosing to publish their work in our open access Wspecial edition on cerebrovascular disease. It would be easy enough for all of them to publish their manuscripts in mainstream print-based journals. The concept of the open access journal: cutting edge, rapid turnaround, readily searchable, is an increased ability to become discerning about the quality of data used to treat patients. We have divided this edition publication of scientific works; is extremely important. With increased access to novel concepts and supporting data, there into three sections dealing with the acute treatment, diagnosis and management, and prognostication of cerebrovascular disease. We hope that these works will fuel critical thinking, novel ideas, healthy debate, and future studies.

Acute Treatment In 1995, the NINDS trial was published and changed the face of acute stroke management, primarily by encouraging rapid evaluation and treatment. When stroke moved from an untreatable to treatable disorder, many studies like the ones following became possible. The inclusion/exclusion criteria for the administration of IV tPA were created as part of the criterion not discussed in the original NINDS paper. In our aging population, cerebral amyloid angiopathy may be an important research protocol and may not all be relevant in current clinical practice. The first paper is an example of a potential exclusion additional trials looking at other interventions (eg., intra-arterial lysis, neuroprotectants, novel thrombolytics such as TNK, factor to consider in treatment of elderly patients with dementia. Since the advent of tPA, there have been a multitude of and the acute use of antiplatelet agents). The second paper illustrates a potential role for clopidogrel loading in patients presenting with stuttering lacunar syndromes. Along with inclusion/exclusion criteria and novel treatments, the diagnostic measures for detecting and assessing severity of is also an evolving field. It is well recognized that along with the posterior circulation, the right hemisphere is grossly underestimated by the NIH Stroke Scale due to difficulty in quickly and accurately evaluating right hemisphere function. Though more difficult to diagnose, lesions of the right hemisphere are no importance of stroke within the right hemisphere, and innovative screening tools for right hemisphere dysfunction. less debilitating, and therefore reperfusion with acute treatment is of utmost importance. The final two papers address the Central Journal of Neurology & Translational Neuroscience

Case Series Special Issue on Cerebral Amyloid Angiopathy: Cerebrovascular Disease Corresponding author Ryan J. Felling, Johns Hopkins University, and Director, A Hidden Risk for IV Pediatric Stroke Program, 200 N. Wolfe Street, Baltimore, MD 21287, Tel: 410-955-4259; Fax: 410-614-9807; E-mail: Thrombolysis? [email protected] Submitted: 12 December 2013 Ryan J. Felling1,3#*, Roland Faigle1#, Cheng-Ying Ho2, Rafael H. Accepted: 20 January 2014 Llinas1 and Victor C. Urrutia1 Published: 28 January 2014 1Department of Neurology, Johns Hopkins University School of Medicine, USA Copyright 2Department of Pathology, Johns Hopkins University School of Medicine, USA © 2014 Felling et al. #These authors contributed equally to this work OPEN ACCESS

Abstract Keywords Recombinant tissue plasminogen activator (t-PA) is the only FDA approved • RT-PA therapy for acute ischemic stroke. Cerebral microbleeds (CMBs) or cerebral amyloid • CAA angiopathy (CAA) are currently not contraindications, however, data regarding this • Microhemorrhage complex issue are limited. We report 2 cases of fatal intracerebral hemorrhage (sICH) • Intracerebral hemorrhage after IV t-PA, each with evidence of CAA. Patients with CAA may have increased risk for IV thrombolysis-associated sICH. We highlight the severe and catastrophic pattern of ICH, which may be a defining characteristic, and discuss the limitations of our current understanding of the risk of thrombolysis-associated ICH in patients with CAA and/ or CMBs.

Introduction Case Presentation Intravenous (IV) thrombolysis with recombinant tissue Case 1 plasminogen activator (t-PA) is the cornerstone of acute ischemic An 81 year old African American woman with , stroke therapy [1]. sICH complicates IV thrombolysis in 4.5 to hyperlipidemia, mellitus, and a prior transient 10% of patients [2,3]. It most commonly occurs in the infarct core ischemic attack presented with the acute onset of right face/ within 36 hours of t-PA administration and remains the most devastating of thrombolysis with an associated mortality rate of up to 47% [4]. MCAarm weakness territory, her and presumptive difficulty speaking. diagnosis Her was NIH ischemic Stroke stroke Scale Cerebral amyloid angiopathy (CAA) is an important cause (NIHSS) was 4. With good localization of symptoms to the left of primary lobar ICH in the elderly [5]. Deposition of amyloid due to multiple vascular risk factors. She did not have a history beta increases the fragility of vessel walls causing spontaneous embolic infarctions. CT scan did not show any hemorrhage. In the of atrial fibrillation, and her symptoms did not suggest multifocal hemorrhages that commonly remain clinically silent. Diagnostic absence of contraindications she received IV t-PA beginning 120 minutes after the onset of symptoms. Her symptoms improved requires pathologic examination. The premortem diagnosis during the infusion, but at the end she developed a moderate criteria for CAA (Boston criteria) exist, but definitive diagnosis CT scan demonstrated multifocal subdural, subarachnoid, and (CMBs) with susceptibility-weighted (or T2*) MRI. The presence intraparenchymalheadache with confusion hemorrhage and (Figure new language 1A). Despite deficits. aggressive Repeat of CMBs CAA reliesis not ona generally identification accepted of lobarpredictor cerebral of increased microbleeds risk medical management, she progressed to herniation and brain for symptomatic ICH after IV thrombolysis, and few studies have prospectively studied this risk. We report 2 cases of sICH leptomeningeal small vessels showed diffuse wall thickening with eosinophilicdeath. On postmortem deposits, and examination, the involved the vessels superficial were cerebral remarkable and for cracking in the wall and replacement of the medial layer by after t-PA, one with pathology-confirmed CAA and another thrombolysis in patients with CAA and propose that IV t-PA may amyloid, creating a “vessel-within-vessel” or “double barreling” with probable CAA. We discuss the risk-benefit analysis of be relatively contraindicated in patients who carry a diagnosis of appearance (Figure 1B, C), consistent with grade 3 CAA [6]. at least probable CAA and/or have a high burden of CMBs. We also draw attention to the catastrophic pattern of these hemorrhages Case 2 and suggest that it may be characteristic of IV t-PA-associated An 84 year old man with hypertension, diabetes mellitus, sICH in the presence of CAA. hyperlipidemia, and dementia presented with acute onset left-

Cite this article: Felling RJ, Faigle R, Ho CY, Llinas RH, Urrutia VC (2014) Cerebral Amyloid Angiopathy: A Hidden Risk for IV Thrombolysis? J Neurol Transl Neurosci 2(1): 1034. Felling et al. (2014) Email: [email protected] Central

thrombolysis in patients with CMBs, but not necessarily CAA. The

the risk of sICH following thrombolysis in patients with CMBs [8]. Alarge, recent prospective meta-analysis BRASIL demonstrated study found ano trend significant toward increase increased in risk of ICH in patients with CMBs, but none of the individual

studiesThere reached are importantstatistical significance limitations [9]. in applying the above evidence to thrombolysis in the setting of acute stroke. First

evidence of CAA in the setting of hemorrhage were done in patientsand foremost, receiving many thrombolysis studies looking for cardiac specifically disease at rather pathologic than stroke, and patients with parenchymal brain injury prior to t-PA administration likely have very different risks of hemorrhage. The

ofstudies the primaryspecifically diagnoses investigating along stroke with hypertensivepatients largely angiopathy, utilize the presence of CMBs which lacks diagnostic specificity. CAA is one Figure 1 (A) CT scan of patient 1 demonstrating multifocal ICH including but the differential diagnosis includes cavernous malformations, subarachnoid, intraparenchymal, and intraventricular components. (B) diffuse axonal injury, and other rare causes. These studies do Hematoxylin and eosin stain demonstrating hemorrhage and “double- not address the burden or location of CMBs which may help to barrel” appearance of vessels in amyloid angiopathy from patient 1. (C) differentiate between etiologies [10]. It is plausible that the Immunohistochemistry demonstrating amyloid beta deposition in the vessel underlying pathology of CMBs relates to the risk of hemorrhage, numerous lobar microhemorrhages. walls of patient 1. (D) Susceptibility-weighted MRI of patient 2 demonstrating after thrombolysis in CAA [11]. and animal models indicate a specific propensity for hemorrhage The cases presented here contribute important additional T showed an old left PCA stroke, but evidence suggesting a relationship between CAA and t-PA- nosided hemorrhage. weakness, He left was gaze presumptively deviation, dysarthria, diagnosed and with neglect. a focal ischemicHis NIHSS stroke was 14. secondary Head C to multiple vascular risk factors. He related sICH. Case 1 is, to our knowledge, the first reported to strongly suggest multifocal embolic . Without makingpathology-confirmed this diagnosis case clinically of CAA in in the t-PA-associated emergency setting hemorrhage as this did not have clinical symptoms or a history of atrial fibrillation contraindications IV t-PA was administered 150 minutes patientin the settingdid not ofhave acute a good stroke, history and of illustrates cognitive decline. the difficulty In order of after symptom onset symptoms. After initial improvement he developed increasing lethargy, nausea, and vomiting 3 hours after the infusion. Repeat head CT demonstrated multifocal burdento differentiate of CMBs risk is associated due to specific with increased underlying risk pathology, of thrombolysis- further ICH. Despite aggressive supportive measures, he suffered brain associatedstudy is warranted sICH. Thisto better will characterize require prospective whether the studies pattern with and herniation and expired. A prior MRI showed extensive lobar CMBs sparing the thalamus, basal ganglia, and pons. With the considering the cost and time delay of pre-treatment MRI versus history of dementia, this is consistent with probable CAA per preventionpre-thrombolysis of sICH. MRI, Meanwhile, and a cost-benefit the potential analysis for increased is necessary, risk Boston criteria (Figure 1D). of t-PA-related sICH in patients with a high probability of CAA Discussion should be an additional factor considered in clinicians’ decisions to treat with thrombolysis. The cases above suggest a possible increased risk of hemorrhagic complications in patients with CAA. Moreover, it References draws attention to the severity of the hemorrhage with multifocal, 1. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick multispace (intraparenchymal, subarachnoid and subdural) JP, et al. Association of outcome with early stroke treatment: pooled distribution, as a possible clinical marker of CAA-associated hemorrhage after IV t-PA. While the hemorrhagic conversion of 2004; 363: 768-774. analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. multifocal embolic strokes could be an alternative explanation 2. for the distribution of hemorrhages, neither patient presented a Intravenous tissue-type plasminogen activator for treatment of acute clinical picture consistent with multifocal strokes, nor did either Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. have a known risk factor for cardioembolic stroke such as atrial stroke: the Standard Treatment with Alteplase to Reverse Stroke 3. (STARS) study. JAMA. 2000; 283: 1145-1150. fibrillation.Evaluating the risk of thrombolysis-related sICH in CAA Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol pathology. In their review, McCarron et al. examined reported 4. Neurosurg Psychiatry. 2008; 79: 1093-1099. is difficult due to the lack of definitive diagnosis without immediate evaluation and management of hyperacute stroke. cases of thrombolysis-associated sICH. Of 50 cases with ICH eNINDSxperience rt-PA at eight Study centers Group and Investigators. implications A for systems community approach practice to 10 had available pathology, with 7 having evidence of CAA [7]. and patient care. the national institute of neurological disorders and Other studies have examined the risk of hemorrhage following

stroke (NINDS) rt-PA stroke study group. Stroke. 1997; 28:1530-1540. J Neurol Transl Neurosci 2(1): 1034 (2014) 2/3 Felling et al. (2014) Email: [email protected] Central

5. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the 9. 6. elderly. Ann Neurol. 2011; 70: 871-880. ischaemic stroke: Systematic review and meta-analysis. J Neurol 1422.Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy. 10. Neurosurg Psychiatry. 2013; 84: 277-2280. Sensitivity and specificity of cortical biopsy. Stroke. 1997; 28: 1418- 7. Rosand J, Muzikansky A, Kumar A, Wisco JJ, Smith EE, Betensky RA, et al. Spatial clustering of hemorrhages in probable cerebral amyloid McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and 11. angiopathy. Ann Neurol. 2005; 58: 459-462. thrombolysis-related intracerebral haemorrhage. Lancet Neurol. Wiessner C, et al. Thrombolysis induces cerebral hemorrhage in a 8. 2004; 3: 484-492. Winkler DT, Biedermann L, Tolnay M, Allegrini PR, Staufenbiel M,

Fiehler J, Albers GW, Boulanger JM, Derex L, Gass A, Hjort N, et mouse model of cerebral amyloid angiopathy. Ann Neurol. 2002; 51: al. risk analysis in stroke imaging before thromboLysis 790-793. (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke. 2007; 38: 2738-2744.

Cite this article Felling RJ, Faigle R, Ho CY, Llinas RH, Urrutia VC (2014) Cerebral Amyloid Angiopathy: A Hidden Risk for IV Thrombolysis? J Neurol Transl Neurosci 2(1): 1034.

J Neurol Transl Neurosci 2(1): 1034 (2014) 3/3 Central Journal of Neurology & Translational Neuroscience

Case Report Special Issue on Stuttering Lacunes: An Acute Cerebrovascular Disease Corresponding author Elisabeth B. Marsh, Department of Neurology, Johns Role for Clopidogrel? Hopkins University, 600 North Wolfe St. Meyer 6-113 Elisabeth B. Marsh* and Rafael H. Llinas Baltimore, MD 21287, USA; Tel: 410-550-0630; Fax: 410- 550-0539; E-mail: [email protected] Department of Neurology, The Johns Hopkins, University School of Medicine, Baltimore, Submitted: 09 December 2013 MD, USA Accepted: 20 January 2014 Published: 28 January 2014 Abstract Copyright Introduction : Intravenous tissue plasminogen activator (IV tPA) has revolutionized © 2014 Marsh et al. the treatment of acute ischemic stroke. However, there remain situations when administration is relatively contraindicated (eg. , arrival outside the accepted treatment OPEN ACCESS window, mild or rapidly improving symptoms). Optimal treatment in these situations is less clear. Case Series: We describe a small case series of 7 patients presenting with fluctuating symptoms concerning for a capsular warning syndrome (acute isolated motor and/or sensory deficits without cortical signs, usually attributed to small vessel pathology), often referred to as a “stuttering lacune”, who were orally loaded with 300mg of clopidogrel. Four of the 7 patients had complete resolution of their symptoms following the load. The others experienced stabilization of their deficits, but were discharged with mild persistent symptoms. Four patients had evidence of diffusion bright lesions on MRI, while the others had no evidence of infarction. None of the patients experienced hemorrhagic conversion of their infarct or other bleeding complications. Conclusion: Our experience suggests that acutely loading with clopidogrel may be both effective and well tolerated in the treatment of stuttering lacunes.

Introduction

Intravenous tissue plasminogen activator (IV tPA) has andright waned. leg became The heavy, following as if morning it was going when to she give noted out from continued under revolutionized the treatment of acute ischemic stroke. However, her. Over the course of the evening these symptoms waxed there remain situations (eg., a patient presents outside the accepted time window or experiences rapid improvement difficulty climbing the stairs she made an appointment with her primary care physician. Her systolic pressure was over contraindicated. Optimal treatment for these patients is less 200mmHg. She was sent to the Emergency Department (ED). In of neurologic deficits), when administration is relatively the ED, her was 228/130 and it was noted that Recurrence (FASTER) trial suggests that administration of ofsymptoms the brain worsenedwas performed with that aggressive showed lowering a diffusion of bright her systolic lesion clear. The Fast Assessment of Stroke and TIA to prevent Early blood pressure to the 130s with intravenous labetalol. An MRI in patients presenting with minor stroke or transient ischemic dual antiplatelet therapy acutely may reduce early recurrence in the left internal capsule with corresponding hypointensity on We describe a small case series of patients presenting andADC management.consistent with On an admission,acute ischemic her stroke NIH Stroke (Figure Scale 1A). wasShe attack (TIA), [1] but was significantly underpowered. was transferred to Johns Hopkins Bayview for further evaluation with fluctuating symptoms concerning for a capsular warning throughout7 for mild dysarthria her hospitalization. and hemiparesis At lower (strength blood pressures, 4 of 5) with she syndrome (acute isolated motor and/or sensory deficits without ataxia; however, symptoms dramatically waxed and waned withcortical 300mg signs, of usuallyclopidogrel. attributed to small vessel pathology) [2], often referred to as a “stuttering lacune”, who were orally loaded developed significant dysarthria, a prominent facial droop, and Case Presentation nodense large hemiparesis vessel . (2 of An5 strength; echocardiogram unable toshowed lift her no arm evidence or leg ofagainst a cardioembolic gravity). A CT source. angiogram Given of her the clinical head and presentation, neck revealed risk transferred from an outside hospital with a waxing and waning factors, and imaging characteristics, it was determined that her ataxicA 53 hemiparesis. year-old woman At noon, with she history noted of that hypertension her right hand was

loadedstroke waswith most 300mg consistent of clopidogrel with a basedsmall vesselon the lacuneFASTER secondary protocol seemed “clumsy. ” She was unable to pick up the phone and to hypertension. Because of her stuttering symptoms, she was her coffee mug “felt funny” when she tried to lift it. At 4PM, her Cite this article: Marsh EB, Llinas RH (2014) Stuttering Lacunes: An Acute Role for Clopidogrel? J Neurol Transl Neurosci 2(1): 1035. Marsh et al. (2014) Email: Central

present with on

often ranging frome of the mild classic to dense lacunar hemiparesis syndromes inas described a matter in of 1982 by C. Miller Fisher [3]. Symptoms wax and wane in intensity- * minutes. Anecdotally, these patients can be misdiagnosed as * having recurrent TIAs. This “stuttering” of symptoms can be distressing to both the patient and physician. Before the results of the IST trial, [4] the capsular warning syndrome was occasionally treated with intravenous heparin. Now antiplatelet therapy is A B used. Despite conventional treatment, the majority of patients go on toThere irreversible is some infarction basis in the and literature significant for clinical the acute deficits treatment [2-3].

of vascular events with 300mg of clopidogrel. In 2001, the Clopidogrel in Unstable Angina to Prevent Recurrent Events * (CURE) trial showed that patients with non-ST elevation * myocardial infarction had better outcomes at one year after an initial load of 300mg of clopidogrel followed by dual antiplatelet therapy, than those treated with aspirin alone [5]. Subsequently, aspirinCLAIR andalone CARESS in large showedvessel cerebrovascular that acute treatment disease resulted with dual in C D antiplatelet therapy (including a 300mg clopidogrel load) versus

Figure 1 fewer microemboli observed by transcranial doppler, a surrogate Diffusion weighted MRIs of Patients 1,3,4, and 7 showing diffusion marker for recurrent stroke risk [6-7]. Unfortunately, both internal capsule consistent with small vessel acute ischemic strokes. An * marks outcomes (too few recurrent strokes observed). bright lesions in: A) internal capsule, B) corona radiata, C) midbrain, and D) the site of diffusion restriction for each case. studies were underpowered to show any difference in clinical

[1]. She had not been on an antiplatelet agent prior to admission. The use of dual antiplatelet therapy in general for secondary Fluctuations in exam ceased following the clopidogrel load. stroke prevention has been more extensively investigated, with mixed results. Multiple large, randomized, placebo controlled studies (CHARISMA, MATCH, ESPS-2, ESPRIT) suggest that Treatment resulted in near complete resolution of her deficits, adding clopidogrel or dypyridamole to aspirin may decrease even at lower systolic blood pressures. She was started on 325mg increasedthe risk of risk recurrent intracranial ischemia, hemorrhage particularly or other in certain severe groups bleeding of of aspirin and a statin for secondary stroke prevention, and was patients; however, the benefit was typically outweighed by the able to be discharged to a rehabilitation facility with only minor Six additional patients have presented to our institution that, even with minor strokes, the rate of increased bleeding over decreased fine motor strength in her right hand. [8-11]. Recently, publication of the results from SPS-3 confirmed NIHSS 3.7) and been loaded with clopidogrel in the acute setting with symptoms consistent with a stuttering lacune (average examineda mean follow-up loading ofwith 3.4 clopidogrel years was faror thegreater role ofthan dual the antiplatelet reduction details summarizing the characteristics of these patients are of recurrent ischemic events [12]. None of these studies summarizedfollowing a head in Table CT to 1.rule Four out ofintracranial the 6 had hemorrhage. complete resolution Further therapy in the acute setting. However, patients with intracranial stenosis enrolled in the SAMMPRIS trial who were treated with of their symptoms (discharge NIHSS 0) following the load. The dual antiplatelet agents along with high dose statin therapy in other two experienced stabilization of their symptoms and the acuteFASTER setting trial had attempted lower rates to show of stroke that recurrenceacute treatment in the withfirst stopped fluctuating, but were discharged with mild persistent 90 days than previously published studies [13]. Additionally, deficits (average NIHSS 1). Following the clopidogrel load, all patients were placed on aspirin 325mg. They underwent a basic dual antiplatelet therapy may improve outcomes for other stroke evidencestroke work-up of diffusion including: neuroimaging, vascular imaging, subtypes by enrolling all patients with “minor strokes” (NIH echocardiography, and laboratory studies. Three patients had Stroke Scale scores of <4). Unfortunately, the study was stopped bright lesions on MRI (Figure 1) while the prematurely secondary to issues with recruitment [1]. others had no evidence of infarction. Following work-up, small vessel pathology was felt to be responsible for the neurologic POINT is a randomized, double-blinded trial designed to symptoms of all 7 patients. All patients were treated according to investigate whether dual antiplatelet therapy acutely in patients ofstandard the patients of care, had including hemorrhagic evaluation conversion by physical, of their occupational, infarct or presenting with minor strokes (NIHSS <4) and TIAs results in otherand speech bleeding therapy. complications. The typical length of stay was 2-3 days. None seriesbetter suchoutcomes. as ours Recruitment to determine is currently the best courseongoing. of Until treatment the data in has been published, we must continue to rely on smaller case Discussion individuals with minor strokes, particularly when they present clopidogrelwith waxing is effective and waning and well symptoms tolerated. and are not good tPA The capsular warning syndrome is a well described clinical candidates. Our experience suggests that acutely loading with phenomenon [2]. Patients, typically with small vessel risk factors, J Neurol Transl Neurosci 2(1): 1035 (2014) 2/4 Marsh et al. (2014) Email: Central

Table 1: Presenting Severity of NIHSS DWI Discharge Patient CharacteristicsAge Race S exof patientsStroke loaded Risk Factorswith clopidogrel. Location Status Symptoms Hemiparesis (worst) Abnormality NIHSS continued ataxic internal *1 53 White Female 10 Yes hand smoking hemiparesis capsule hypertension, weakness 2/5 2 Black numbness and 3 No none resolved 0 cocaine use, smoking hemi-body hypertension, hemiparesis 2 58 Male 4/5 continued 3 57 W F migraine, PFO Yes corona radiata 1 hemiparesis arm weakness dysarthria, improvement diplopia, 2/5 8 55 W diabetes, smoking 3 Yes midbrain of 1 hemiparesis hemiparesis 4 M 4/5 5 BF diabetes, cocaine use, 3 No none resolved 0 hypertension, hemiparesis smoking dysarthria, 52 4/5 6 W none resolved 0 hypertension, diabetes, smoking clumsy hand, 78 M hyperlipidemia, 4/5 2 CT only dysarthria internal 7 W hemiparesis 3 Yes resolved 0 capsule hypertension,smoking 64 M hyperlipidemia, 4/5

*RepresentativeIt is possible Case that the patients in our series would have ischaemic atta

ck to prevent early recurrence (FASTER): a randomised However, the natural histor symptomatically improved on their own without treatment. controlled pilot trial. Lancet Neurol. 2007; 6: 961-969. lacunes do tend to recover welly of capsular over the warning long term; syndromes however, is we to 2. Donnan GA, O’Malley HM, Quang L, Hurley S, Bladin PF. The capsular progress to infarction [2-3]. Patients presenting with small deep warning syndrome: pathogenesis and clinical features. Neurology. 3. 1993; 43: 957-962. would argue that they commonly require short term physical Fisher CM. Lacunar strokes and infarcts: a review. Neurology. 1982; therapy. The majority of our patients who were loaded with 32: 871-876. clopidogrel left the hospital completely, or nearly symptom free. is unclear. In general, small strokes are believed to have 4. [Nopatients authors with listed] acute The ischaemic International stroke. Stroke International Trial (IST): a Strokerandomised Trial The risk of bleeding secondary to loading with clopidogrel trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients that we have treated to date experienced intracranial a lower risk of hemorrhagic conversion [14]. None of the 5. Collaborative Group. Lancet. 1997; 349: 1569-1581. Effects of clopidogrel in addition to aspirin in patients with acute and then treating with aspirin alone rather than continuing dual Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK et al. hemorrhage. Additionally, by loading acutely with clopidogrel without assuming the increased bleeding risk over the long term coronary syndromes without ST-segment elevation. N Engl J Med. seenantiplatelet in previous therapy, studies. we derive the benefit of the initial load 6. 2001; 345: 494-502.

Wong KSL, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin small number of patients who were not randomized. The average alone for reducing embolization in patients with acute symptomatic Our case series is not without limitations. It is based on only a cerebral or carotid stenosis (CLAIR study): a randomized, drug use, smoking, and other vascular risk factors are prevalent 7. open-label, blinded-endpoint trial. Lancet Neurol. 2010; 9: 489-497. age was also only 59.6 years. Though hypertension, hyperlidemia, in our population, and lacunar strokes in this age group are not Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: uncommon, the younger age of our patients may result in poor the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic generalizability, and raises the question of whether higher rates Carotid Stenosis (CARESS) trial. Circulation. 2005; 111: 2233-2240. of hemorrhagic conversion may be seen in older individuals [14]. in patients who do not meet criteria for treatment with IV 8. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. In conclusion, for stuttering small vessel lacunar syndromes Clopidogrel and aspirin versus aspirin alone for the prevention of our small case series it appeared to be both effective and well 9. atherothrombotic events. N Engl J Med. 2006; 354: 1706-1717. tPA, there may be a role for orally loading with clopidogrel. In tolerated. We await the results of POINT to elucidate the issue Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste further. M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high- References risk patients (MATCH): randomised, double-blind, placebo-controlled 1. 10. trial. Lancet. 2004; 364: 331-337. ; FASTER Investigators. Fast assessment of stroke and transient Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. AM European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic J Neurol Transl Neurosci 2(1): 1035 (2014) 3/4 Marsh et al. (2014) Email: Central

13.

acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143: Henkes H, Bäzner H, Nelson PK. Comment on: Stenting versus 11. 1-13. aggressive medical therapy for intracranial arterial stenosis : Chimowitz MI, Lynn MJ, Derdeyn CP, et al. N Engl J Med. 2011;365:993- ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, 1003. Clin Neuroradiol. 2011; 21: 257-259. Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral transformation in patients with acute ischaemic stroke and an ischaemia of arterial origin (ESPRIT): randomised controlled trial. 14. Marsh EB, Llinas RH, Hillis AE, Gottesman RF. Hemorrhagic Lancet. 2006; 367: 1665-1673. indication for anticoagulation. Eur J Neurol. 2013; 20: 962-967. 12. SPS3 Investigators, Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012; 367: 817-825.

Cite this article Marsh EB, Llinas RH (2014) Stuttering Lacunes: An Acute Role for Clopidogrel? J Neurol Transl Neurosci 2(1): 1035.

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Research Article Special Issue on Right Hemisphere Ischemia is Cerebrovascular Disease Corresponding author Carolyn A. Cronin, University of Maryland School of more likely to Cause Falsely Medicine, 110 South Paca Street, 3rd floor,Baltimore, MD 21201, Tel: 410-328-3871; Fax: 410-328-5899; Email: “Mild” Symptoms and Poor [email protected] Submitted: 25 November 2013 Accepted: 20 January 2014 Outcomes without Thrombolysis Published: 28 January 2014 Carolyn A. Cronin1* and Lisa D. Hermann2 Copyright © 2014 Cronin et al. 1Department of Neurology, University of Maryland School of Medicine, USA 2 Department of Neurology, Vanderbilt University, USA OPEN ACCESS

Abstract Keywords • Stroke Background: Rapidly improving or mild symptoms is the most common reason • Throbolytic therapy that acute stroke patients arriving within the approved time window are not treated • IV tPA with intravenous tissue-type plasminogen activator (IV tPA). We reviewed outcomes at discharge for patients excluded from IV tPA because of rapidly improving or mild symptoms, with the aim of being better able to identify patients who may benefit from thrombolysis. Methods: All patients between April 2006 and June 2010 from our center who did not receive IV tPA with “rapidly improving or mild symptoms” as the reason for exclusion were identified. Poor outcome was defined as hospital discharge to location other than home or inability to ambulate independently at discharge. Results: There were 66 patients excluded from tPA treatment because of rapidly improving or mild symptoms. Eleven patients (16.7%) had poor outcomes. In 6 patients (9%), poor outcome was due to neurologic deficit. All 6 patients with neurologic deficits had right hemisphere strokes, and one also had cerebellar infarcts. Conclusions: Patients presenting with rapidly improving or mild symptoms do not universally have good outcomes. This may be particularly true in the case of right hemispheric ischemia where deficits are not fully reflected by NIHSS score. If a patient with a low NIHSS score is otherwise a candidate for tPA, a more detailed exam is warranted to better identify potentially disabling deficits that might benefit from thrombolysis.

Abbreviations We reviewed outcomes of consecutive patients from a single center who did not receive thrombolytic therapy with “rapidly : Intravenous recombinant tissue plasminogen IV tPA improving or minor symptoms” as the reason for exclusion from activator; GWTG: Get with the Guidelines database; NIHSS: treatment, with the aim of being better able to identify patients in National Institutes of Health Stroke Scales Introduction thisMet grouphods who may benefit from thrombolysis. Intravenous recombinant tissue plasminogen activator (IV tPA) remains the only approved treatment for acute ischemic We used the AHA/ASA “Get with the Guidelines” (GWTG) stroke. Despite its approval for use in stroke for 15 years, only database to identify consecutive acute ischemic stroke patients 3.4% to 5.2% of patients with acute stroke receive tPA [1]. The between April 2006 and June 2010 from University of Maryland most common reason patients are excluded from treatment, Medical Center who did not receive IV tPA. The GWTG data in when they arrive within the approved time window, is “rapid combination with the medical record were reviewed to identify improvement or stroke severity too mild.” [2-5]. It has previously those patients with “rapid improvement or stroke severity been found that patients excluded from IV thrombolysis for too mild” as the only reason documented by the treating mild or rapidly improving symptoms do not universally have a vascular neurologist for exclusion from thrombolytic therapy. benign course [6-9]. As many as 20-32% have a poor outcome at discharge. with more severe symptoms prior to time of thrombolytic If the documentation indicated fluctuation of symptoms,

Cite this article: Cronin CA, Hermann LD (2014) Right Hemisphere Ischemia is more likely to Cause Falsely “Mild” Symptoms and Poor Outcomes without Thrombolysis J Neurol Transl Neurosci 2(1): 1036. Cronin et al. (2014) Email: [email protected] Central treatment decision, patients were considered to be in the “rapid hemisphere infarcts. Patient 6 had a right frontal lobe infarct and improvement” subset. Demographic data, stroke risk factors, also a left superior cerebellar infarct, which required a posterior baseline National Institutes of Health Stroke Scale (NIHSS) craniotomy and decompression to treat malignant cerebellar scores, discharge location and ambulatory status were recorded edema. prospectively in the GWTG database and extracted for this Of the 6 patients with poor outcome due to continued study. The medical records of patients with poor outcome were reviewed retrospectively to determine details of hospital course, infarct location, and reasons for poor outcome. Poor outcome neurologic deficit, 4 had improving deficits and 2 had consistently onsetmild deficits, to the timewhereas of evaluation all 5 of the for patients thrombolytic with non-neurologic therapy. This inability to ambulate independently at discharge. Patients were trendreason toward for poor patients outcome with had poor consistently outcome being mild more deficits likely from to consideredwas defined toas havehospital a non-neurologic discharge to location reason other for poor than outcomehome or if hospital notes documented no or only very minor residual forhave this improving trend toward rather worse than outcome consistently in the mild “rapidly deficits improving” was not primary factors in patient not being discharged to home. statistically significant due to small numbers. Possible reasons neurological deficits and other medical or social reasons as the group include: overly optimistic interpretation of the degree Differences between the groups were assessed using the of improvement or assumption that improvement seen would two-tailed Fisher exact test for dichotomous variables and continue rather than plateau, or patients with more severe the unpaired t-test for continuous variables with the InStat 3 program (version 3.1a; Graph Pad Software). lackdeficits of detailed at some documentation point being more of serialprone examinations. to worsen back to prior Results and Discussion deficit severity. We were unable to explore this further due to The predominance of right hemisphere infarcts in our patients During the study period, 1036 patients with acute ischemic stroke were admitted to our center. Of those, 168 patients (16%) predictors of poor outcome at discharge in patients excluded were treated with IV tPA. There were 66 patients excluded fromwith poor thrombolysis outcomes fordue improvingto neurologic or deficit mild symptoms is striking. include:Known from treatment with IV tPA for “rapid improvement or stroke severity too mild”. Eleven (16.7%) of those patients had poor large vessel occlusion [7,8]. We know of no previous studies reportingan initial NIHSS right hemisphere≥10 with rapid localization improvement, as a possible and a persistent predictor in comparison to patients with good outcomes (mean age 72.4 outcomes. Patients with poor outcomes were significantly older of poor outcome in this patient population. It has been shown that the NIHSS assigns more points for equal volume infarcts of differences in baseline characteristics (Table 1). years vs. 63 years; p=0.0021), but there were no other significant left hemisphere compared to the right [10,11]. Therefore, a low Of the 11 patients with poor outcome, 5 were attributed NIHSS may conceal a large right hemisphere stroke burden that to deconditioning and poor general medical condition and could result in poor outcome if not treated. A study comparing baseline NIHSS score and long term outcome showed this may also be true for posterior circulation strokes, as patients had a 6 to continued neurologic deficits (Table 2). All six patients withTable continued1: Patient Characteristics. neurologic deficit and poor outcome had right Total Good Poor p n (%) 66 55 (83.3) 11 (16.7) Age (y) 63 61 72.4 0.0021 Male Gender 29 (43.9%) 26 (47.2%) 3 (27.3%) 0.323 Ethnicity White 34 (51.5%) 30 (54.5%) 4 (36.4%) 0.333 Non-White 27 (40.9%) 25 (45.5%) 7 (63.6%) Time to Presentation (min) 93.4 96.4 78.4 0.2521 NIHSS (mean) 2.7 2.6 3.1 0.6543 Rapid Improvement 24 (36.4%) 20 (36.4%) 4 (36.4%) 1.000 Hypertension 49 (74.2%) 40 (72.7%) 9 (81.8%) 0.713 Hyperlipidemia 28 (42.4%) 25 (45.5%) 3 (27.3%) 0.331 Diabetes Mellitus Type 2 15 (22.7%) 11 (20.0%) 4 (36.4%) 0.254 Smoker 24 (36.4%) 18 (32.7%) 6 (54.5%) 0.189 17 (25.8%) 14 (25.5%) 3 (27.3%) 1.000 Atrial Fibrillation 9 (13.6%) 7 (12.7%) 2 (18.2%) 0.638 CHF 1 (1.5%) 1 (1.8%) 0 1.000 Prior stroke 18 (27.3%) 13 (23.6%) 5 (45.5%) 0.155 Abbreviations: NIHSS: National Institutes of Health Stroke Scales; CHF: Congestive Heart Failure.

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Table 2: Patients with Poor Outcome. Rapidly Discharge Pt. Age Sex NIHSS Location of Stroke Reason for Poor Outcome Improving Location 5: 2 gaze 1 70 M 1 LUE Yes Acute Rehab Right MCA 2 LLE 7: 2 LOC Continued Neurologic Deficit 2 VF 2 74 F Yes Acute Rehab Presumed Right MCA 2 face 1 dysarthria Continued Neurologic Deficit 2: 1 face 3 80 F Yes Acute Rehab Right parietal lobe 1 neglect 5: 1 face Home with Right Corona Radiata and Continued Neurologic Deficit 4 68 F 1 LUE 2 RUE Yes assistance External Capsule 1 sensory 5: 1 RUE, 1 RLE Right thalamus and Continued Neurologic Deficit 5 67 F 1 LUE, 1 LLE No Acute Rehab posterior limb of internal 1 neglect capsule 2: 1 sensory L Superior Cerebellum Continued Neurologic Deficit 6 54 M No Acute Rehab 1 dysarthriaa R Frontal Lobe posterior craniotomy Worsening of neurologic deficits; 7 79 F 1: 1 face No Acute Rehab Right MCA Deconditioning 2: 1 face 8 73 F No Acute Rehab TIA Deconditioning 1 dysarthria 9 79 M 2: 2 gaze No Acute Rehab Right Frontal Lobe Deconditioning 3: 1 face 1 RUE Home with Deconditioning 10 87 F No Left Thalamus 1 RLE assistance Family declined rehab 11 79 F 0 No Acute Rehab TIA Deconditioning

Abbreviations: NIHSS: National Institutes of Health Stroke Scales; L(R)UE: left (right) upper extremity; L(R)LE: left (right) lower extremity; LOC: level of consciousness, VF: TIA: transient ischemic attack. higher probability of an visualunfavorable fields; outcome with relatively low not picked up on the initial NIHSS but may still contribute to NIHSS scores in the posterior circulation compared to anterior disability. Treatment with tPA for patients with mild stroke has [12]. been found to be safe, supporting more liberal treatment in this patient population [13,14]. Recent analysis estimated that about 2000 patients per year would not be disabled (with a savings difference between patients with good vs. poor outcome. This of $200 million/year) if patients with NIHSS less than 5, and mayAge represent was the a bias only against baseline giving characteristic IV tPA in elderly with apatients. significant Or otherwise eligible, were treated with tPA [15]. More research is needed to help guide treatment in this large group of stroke with older patients generally doing worse regardless of the it could reflect the poorer baseline medical status in the elderly, patients. patients with poor outcome it was due to general deconditioning References intervention. This is supported by our finding that in five of the 11 1. ratherIn agreement than specific with new prior neurologic reports, deficits. we found rapidly improving type plasminogen activator use for ischemic stroke in the United patients and patients with continuously mild symptoms may States:Adeoye a O,doubling Hornung of treatmentR, Khatri P,rates Kleindorfer over the course D. Recombinant of 5 years. Stroke.tissue- not be at equal risk for poor outcomes [7,8]. At the time when 2011; 42: 1952-1955. the patients in this study were entered into the Get with the 2. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke Guidelines database, the “mild” and “rapidly improving” reasons patients excluded from TPA therapy? An analysis of patient eligibility. for not treating with tPA were combined into one data point. Since Neurology. 2001; 56: 1015-1020. then, they have been separated into two different categories. So, outcomes in these patients can be more easily tracked going 3. al. Eligibility for recombinant tissue plasminogen activator in acute ischemicKleindorfer stroke: D, Kissela a population-based B, Schneider study.A, Woo Stroke. D, Khoury 2004; J, 35: Miller e27-29. R, et the use of a retrospective chart review and small numbers. forward to confirm this finding. Limitations of our study include 4. García-Moncó JC, Pinedo A, Escalza I, Ferreira E, Foncea N, Gómez- Conclusion Beldarrain M, et al. Analysis of the reasons for exclusion from tPA therapy after early arrival in acute stroke patients. Clin Neurol threshold when making treatment decisions, especially for Neurosurg. 2007; 109: 50-53. Our findings support the practice of not using a strict NIHSS patients who present with non-dominant hemisphere symptoms. 5. Before the decision is made to withhold thrombolytics because et al. Strokes With Minor Symptoms: An Exploratory Analysis of the the symptoms are “mild” or “rapidly improving”, a more detailed NationalKhatri P, Institute Kleindorf ofer Neurological DO, Yeatts SD,Disorders Saver JL,and Levine stroke SR, Recombinant Lyden PD, Tissue Plasminogen Activator Trials. Stroke. 2010; 41: 2581-2586. exam may be warranted to better assess for deficits that are J Neurol Transl Neurosci 2(1): 1036 (2014) 3/4 Cronin et al. (2014) Email: [email protected] Central

6. strokes? NINDS t-PA Stroke Study Group. Stroke. 1999; 30: 2355- Schwamm LH.Poor Outcomes in Patients Who Do Not Receive 2359. IntravenousSmith EE, Abdullah Tissue AR, Plasminogen Petkovska Activator I, Rosenthal Because E, Koroshetz of Mild WJ, or 12. Improving ischemic Stroke. Stroke 2005; 36: 2497-2499. the association of National Institutes of Health Stroke Scale scores and 7. acuteFink JN, magnetic Selim MH, resonance Kumar imagingS, Silver strokeB, Linfante volume I, Caplan equal forLR, patientset al. Is Vinuela F, et. al. Early MRI and Outcomes of Untreated Patients with with right- and left-hemisphere ischemic stroke? Stroke. 2002; 33: MildRajajee or ImprovingV, Kidwell C,Ischemic Starkman Stroke. S, Ovbiagele Neurology B, Alger2006; JR,67: Villablanca 980-984. P, 954-958. 8. 13. U, et al. Outcome of stroke with mild or rapidly improving symptoms. Baseline NIH Stroke Scale Score predicting outcome in anterior and Stroke.Nedeltchev 2007; K, 38: Schwegler 2531-2535. B, Haefeli T, Brekenfeld C, Gralla J, Fischer posteriorSato S, Toyoda circulation K, Uehara strokes. T, Toratani Neurology. N, 2008;Yokota 70: C, 2371-2377.Moriwaki H, et al. 9. Ozdemir O, Beletsky V, Chan R, Hachinski V. Thrombolysis in patients 14. Urra X, Ariño H, Llull L, Amaro S, Obach V, Cervera Á, et al. The outcome of patients with mild stroke improves after treatment with systemic ischemia. Arch Neurol. 2008; 65: 1041-1043. thrombolysis. PLoS One. 2013; 8: e59420. with marked clinical fluctuations in neurologic status due to cerebral 10. Smith EE, Fonarow GC, Reeves MJ, Cox M, Olson DM, Hernandez AF, 15. et al. Outcomes in mild or Rapidly Improving Stroke Not Treated R, et al. Safety and outcome after thrombolysis in stroke patients with with Intravenous Recombinant Tissue-Type Plasminogen Activator. mildKöhrmann symptoms. M, Nowe Cerebrovasc T, Huttner Dis. HB, 2009; Engelhorn 27: 160-166. T, Struffert T, Kollmar Stroke. 2011; 42: 3110-3115. 16. 11. Effective Acute Treatment for Mild Ischemic Strokes. Stroke 2011; 42: the National Institutes of Health Stroke Scale favor left hemisphere Khatri,e66. P., Khoury JC, Alwell K, et. al. The Public Health Impact of an Woo D, Broderick JP, Kothari RU, Lu M, Brott T, Lyden PD, et al. Does

Cite this article Cronin CA, Hermann LD (2014) Right Hemisphere Ischemia is more likely to Cause Falsely “Mild” Symptoms and Poor Outcomes without Thrombolysis J Neurol Transl Neurosci 2(1): 1036.

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Research Article Special Issue on Right Hemisphere Dysfunction Cerebrovascular Disease Corresponding author Argye E. Hillis, Phipps 446; 600 N. Wolfe Street; Johns is Better Predicted by Hopkins University School of Medicine; Baltimore, MD, USA 21287; Tel: 410-614-2381; Fax: 410-614-9807; E-mail: Emotional Prosody Impairments [email protected] Submitted: 16 December 2013 Accepted: 20 January 2014 as Compared to Neglect Published: 28 January 2014 Chinar Dara1, Jee Bang1, Rebecca F. Gottesman1,2 and Argye E. Copyright © 2014 Hillis et al. Hillis1,3,4* 1Departments of Neurology Johns Hopkins University School of Medicine, Baltimore, MD, USA OPEN ACCESS 2Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University; Baltimore, MD, USA Keywords 3Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, • Prosody Baltimore, MD, USA • Neglect 4Department of Cognitive Science, Johns Hopkins University, Baltimore, MD, USA • Emotions • Stroke • Right hemisphere Abstract • Communication Background: Neurologists generally consider hemispatial neglect to be the primary cognitive deficit following right hemisphere lesions. However, the right hemisphere has a critical role in many cognitive, communication and social functions; for example, in processing emotional prosody (tone of voice). We tested the hypothesis that impaired recognition of emotional prosody is a more accurate indicator of right hemisphere dysfunction than is neglect. Methods: We tested 28 right hemisphere stroke (RHS) patients and 24 hospitalized age and education matched controls with MRI, prosody testing and a hemispatial neglect battery. Emotion categorization tasks assessed recognition of emotions from prosodic cues. Receiver operating characteristic (ROC) analyses were used to compare tests in their ability to distinguish stroke patients from controls. Results: ROC analyses revealed that the Prosody Score was more effective than the Neglect Battery Score in distinguishing stroke patients from controls, as measured by area under the curve (AUC) ; Prosody Score = 0.84; Neglect Battery Score =0.57. The Prosody Score correctly classified 78.9%, while Neglect Score correctly classified 55.8% of participants as patients versus controls. The Prosody Score was similar to the total NIH Stroke Scale in identifying RHS patients (AUC=0.86, correctly classifying 80.1% of patients versus controls), but the tests only partially overlapped in the patients identified. Conclusions: Severe prosody impairment may be a better indicator of right hemisphere dysfunction than neglect. Larger studies are needed to determine if including a bedside test of Prosody with the NIH Stroke Scale would most efficiently and reliably identify right hemisphere ischemia.

Abbreviations ADC: AUC: Area Under deficits following right hemisphere stroke are unilateral DWI FLAIR: spatial neglect (USN) and extinction with double simultaneous Apparent Diffusion Coefficient;NIHSS stimulation [1]. USN is typically defined as an inability to detect, the Curve; : DiffusionRHS Weighted Imaging; ROC fluid attend or respond to stimuli on the side of space contralateral attenuation inversion USN: recovery; : National Institutes of to brain damage, while detecting and responding to stimuli Health Stroke Scale; : right hemisphere stroke; : Receiver on the ipsilesional side [2]. Approximately 25-30% of acute IOperatingntroduc Curve;tion Unilateral spatial neglect; right hemisphere stroke patients have USN [3]. The only “right hemisphere” cognitive deficits evaluated by the NIH Stroke Scale (NIHSS) are neglect and extinction [4]. One limitation of this fact It is generally believed that the most common cognitive is that the NIHSS may be less sensitive to right hemisphere than Cite this article: Dara C, Bang J, Gottesman RF, Hillis AE (2014) Right Hemisphere Dysfunction is Better Predicted by Emotional Prosody Impairments as Compared to Neglect. J Neurol Transl Neurosci 2(1): 1037. Hillis et al. (2014) Email: [email protected] Central

left hemisphere stroke, or may underestimate the volume of right included: Axial diffusion weighted imaging (DWI) trace sequences hemisphere stroke [4]. and apparent diffusion coefficient (ADC) maps, fluid attenuation inversion recovery (FLAIR) to evaluate for old strokes, However, the right hemisphere has other cognitive functions susceptibility weighted images to evaluate for hemorrhage, and that are less widely recognized that may be at least equally T2 weighted sequences to evaluate for other lesions. Technicians important from a functional standpoint and may provide clinical masked to behavioral assessment measured volume of infarct on markers that are more reliable than USN for indicating the DWI.Exp erimental Tasks presence or severity of right hemisphere stroke (RHS). Adding evaluation of such cognitive functions could improve detection Emotional prosody tasks and evaluation of outcome of RHS. For example, the right hemisphere is critical for emotional prosody (expression or comprehension of emotional meaning through speech prosody, Two categorization tasks evaluated emotional processing such as variations in pitch, intensity, and rate). Individuals for prosodic features alone. In the word identification task with right hemisphere lesions have shown difficulty identifying (word ID), participants were presented utterances that were emotions (such as happy, angry, sad, and fearful) of the speaker semantically neutral but communicated specific emotions during human communication. The predominant role of the right through the prosody (e. g. , I am going to the other movies). In the hemisphere in processing emotional prosody is corroborated monosyllabic identification task (monosyllabic ID), participants by studies recording event-related brain potentials [5]; fMRI were presented with monosyllabic utterances that conveyed studies showing right hemisphere activation in association specific emotions through prosody (e. g. , ba ba ba ba ba ba ba). with prosody judgments [6,7]; a left ear advantage for prosody In word and monosyllabic ID tasks, participants listened to each using the dichotic listening paradigm [8,9]; and lesion studies utterance (from an audio file) and then identified the emotion of judging emotional meaning from prosody [10-14]. There are of the speaker based on the prosodic features in a six forced- a number of other “right hemisphere deficits” that have clear choice response format (alternatives - happy, surprise, angry, functional consequences, such as anosognosia and apathy (see, sad, disinterest, neutral) presented as a picture and as a word 15, 16), integration of information to comprehend discourse, on a laptop or on paper. Stimuli for each of these tasks were interpret metaphor, draw inferences, and so on (see, 17) for specifically developed to assess comprehension of emotional review). It is also crucial for both affective empathy (the ability prosody in patients as well as healthy adults and this type of to recognize and respond to affective experiences of another stimuli has been used successfully in previous studies [14,20]. person; (18, 19) and cognitive empathy (the ability to take the The administration time for these two tasks ranged from 5.4 to perspective of another person). However, impairments in many 7.6Neglect minutes. tasks of these cognitive functions are difficult to objectively quantify on a scale of more than a few points. One reason USN may have been used so frequently as the primary marker of right hemisphere Hemispatial neglect tests administered as part of the Stroke cognitive function is that it is relatively easy to measure the Cognitive Outcomes and REcovery (SCORE) study included: [1] severity with a variety of bedside pencil and paper, computer, copy scene (copying the “Ogden scene”: a house, a fence, and or other standardized tests. We hypothesized that impairment two trees; there are 36 total components to the picture, so each in comprehension of emotional prosody, which can also be missing component yields a percent error) ; [2] a gap detection measured on a scale of 0-100% accuracy on objective and reliable test (identifying the gaps in small and large circles (21). In this tests,Materi is evenal mores a nsensitived met andho specificds for RHS than is USN. test, a sheet of paper filled with 10 whole circles, 10 circles Participants with gaps on the left, and 10 circles with gaps on the right was presented to the patient. Patients were instructed to cross out the circles with the gaps and to circle the full circles on the paper. This test was administered at midline of the patient’s body. For each A series of 28 patients with acute RHS (mean age 55 years task, the number of errors and the total number of stimuli were old and mean education 14 years) and 24 patients with transient tabulated. Errors on each side of the page and/or stimulus were ischemic attacks (TIA) admitted to Johns Hopkins Hospital, recorded in order to distinguish between viewer- and stimulus- Baltimore, USA were recruited for this study. TIA participants centered neglect. The test is administered twice, once with large were included as age and education matched controls without circles, and once with smaller circles. The administration time evidence of brain lesion on MRI and resolution of presenting for these tasks ranged from 2.9 to 5.8 minutes. Error rate on the symptoms at the time of testing, but with similar socioeconomic SCORE neglect tests potentially ranged from 0-100%. background as the stroke patients and same testing environment as the stroke patients. All patients were examined on the clinical Neglect and extinction as scored on the NIH Stroke Scale and behavioral tests within 48 hours from the admission (NIHSS) were also recorded for each patient. The NIHSS scores to the hospital. Exclusion criteria included: bilateral brain were obtained by reading through the admission history and damage, injury to brainstem/cerebellum, history of other major physical notes, progress notes from the first full day of admission, neurological or psychiatric illness or previous stroke, and positive and discharge summaries. If NIHSS was not documented, a toxicology screens for drugs of abuse or alcohol. retrospective NIHSS was calculated using the algorithm used by Williams et al. , 2000 [22]. Neglect is assessed on the basis of Imaging: Lesion location for all patients was identified by describing a complex picture, reading words and sentences, and the neuroradiologist and technicians on MRI sequences, which eye movements (pursuits). Extinction is assessed with double J Neurol Transl Neurosci 2(1): 1037 (2014) 2/7 Hillis et al. (2014) Email: [email protected] Central

F p F p simultaneous stimulation in tactile and visual modalities. Each Group, [1,50] = 29.22, < 0.00001 and a main effect of Prosody, participant was scored as having neglect [0-1], extinction [0-1] [1,50] = 8.51, < 0.01. Post-hoc Tukey’s (HSD) inspection of orProcedure both (maximum of 2 possible points). the group effect revealed that the RHS patients (M=0.49% errors) made significantly more errors than the TIA group (M=0.25% errors). Also, the prosody main effect showed that both the Ethical approval of the study was obtained from the Johns groups tend to make more errors in the prosody word ID task Hopkins Institutional Review Board, and informed written (M=0.43% errors) as compared to the monosyllabic ID task consent was obtained from all participants prior to testing. (M=0.33% errors). A 2 x 2 ANOVA with factors of Group (RHS, Participants were tested in their individual rooms in the Stroke TIA) and SCORE Neglect (viewer-centered, stimulus-centered) ward. Testing was carried out in one session; these tests were did not reveal any main or significant effects. The neglect scores part of a larger battery that included assessment of prosody from the NIHSS were also similar. Out of 28 patients, 3 patients production and imitation, as well as other cognitive assessments. showed signs of neglect, 5 patients showed signs of extinction, Auditory stimuli were presented by a laptop over headphones and 2 patients had both neglect and extinction. All individuals controlled by Presentation software (NeuroBehavioral Systems, with neglect on either test also had impaired prosody. A summary USA). Stimuli within each task were randomized and then played of the mean error rate for the prosody and SCORE neglect tasks is over high quality, volume adjustable headphones at a comfortable shown in the table 1. listening level. They were instructed to listen carefully to each The ROC analysis showed that the Prosody Score was utterance and then make a judgment about the emotion of the more effective than the SCORE Neglect Score in distinguishing speaker. Most patients responded by pressing a button on a Cedrus stroke patients from controls, as measured by the ROC curve 730 response box. For these patients, the response alternatives (AUC for the overall Prosody Score = 0.84; AUC for the overall (verbal labels) were presented centrally on the computer screen Neglect Score = 0.57). The overall Prosody score of >31% error as well as marked on the response box. However, for the initial correctly classified 78.9% of the participants versus controls. 18 patients, response alternatives were presented on paper, and For the overall Prosody score, the sensitivity was 92.9% and the the patient simply pointed to the emotion of the speaker. There specificity was 62.5%. For the prosody word ID task, an error was no time limitation for the participants and the next trial was rate of > 37% had a sensitivity of 82.1% and specificity of 66.7% presented only after the participant had provided a response. (correctly classifying 75% of participants as patients versus There was not a marked difference in the administration time controls). An error rate of > 33% on the prosody monosyllabic for the two subtests when the paper version was used versus the ID task had a sensitivity of 78.6% and specificity of 79.2% computerStatistical version. analyses (correctly classifying 78.9% of participants as patients versus controls) ; ROC curves are shown in Figure 1. In contrast, the AUC for SCORE neglect summary score was 0.55 for both viewer- Firstly, to examine the performance of the two participant centered and stimulus-centered neglect measures. At most, the groups (RHS, TIA), two 2 x 2 ANOVAs were conducted separately SCORE Neglect Score could classify 55.8% of patients vs. controls. for prosody identification and neglect tasks. Secondly, Receiver Of 28 RHS patients, only 5 (17.9%) patients made fewer errors Operating Characteristic (ROC) analyses were conducted to than the cut-off point on the prosody word ID task and 6 (21.4%) identify a more accurate cut-off point that could help identify the patients made fewer errors than the cut-off point on the prosody probability of disease in individual participants [23]. ROC curves monosyllabic ID task; whereas 24 (85.7%) patients made 0% were created by plotting the range of sensitivity and specificity errors on the SCORE Neglect tests. The possible range of cut-off pairs for each participant’s error rate, with case status (stroke points for the sensitivity and specificity for prosody scores on the versus TIA) as the classifier variable. A global assessment of two ID tasks and neglect measures are shown in Figure 1. the performance of the test is given by the area under the ROC curve (AUC). That is, AUC provides an estimate of the accuracy The AUC for NIHSS Neglect was 0.63 and for Extinction was of the diagnostic test in discriminating between the patients 0.57, and for both was 0.66. Again, prosody was significantly and controls. AUC’s were compared for different tests in their better than NIHSS neglect/extinction in distinguishing stroke characteristics relative to case status. In addition to the AUC, patients from controls in this study. Using quintile scores for when evaluating the usefulness of a screening measure to identify Prosody Recognition (so that they would have similar scales, those individuals with cognitive impairment, the cut-off point rather than comparing a 100 point continuous scale to a 3 point would be chosen to ensure that most cases were detected (high scale), the AUC for Prosody was significantly2 higher than the sensitivity; >80% is desirable) but not at the cost of many false NIHSS neglect/extinction score of 0-2 (χ = 4.0; p= 0.047). positives (goal specificity; >60% is acceptable; 24). Therefore, The SCORE neglect tests identified three stroke patients with cut-offs were selected that maximized the sensitivity (>80%) of neglect who were not identified by the NIHSS as having neglect, the tests while maintaining an acceptably low false positive rate but two were identified as having extinction on the NIHSS. The (specificityResults > a 60%).nd D iscussion NIHSS identified 7 participants as having extinction, but one was Results a control. The AUC for the total NIHSS score was 0.86; it classified 80.8% of patients. Three patients were detected with prosody A 2 x 2 ANOVA with factors of Group (RHS, TIA) and Prosody who were not detected with NIHSS; both had cortical strokes (word ID, monosyllabic ID) revealed a significant main effect of (two parietal, one frontal). Two patients were detected with J Neurol Transl Neurosci 2(1): 1037 (2014) 3/7 Hillis et al. (2014) Email: [email protected] Central

Table 1:

Demographics and mean error rates on the prosody and neglect tasksProsody for RHS ID and control participants. Neglect Participants Age Education Sex Viewer Stimulus word monosyllabic Centered Centered

RHS (n=28) 55.93 13.62 12 female 0.54 0.43 0.01 0.02 SD 11.69 2.94 0.19 0.22 0.06 0.07 Controls(n=24) 51.71 13.33 16 female 0.30 0.21 0.00 0.00 SD 10.11 3.95 0.22 0.12 0.00 0.00 Abbreviations: SD: standard deviation

Figure 1 ROC curve plots for the prosody and neglect tasks.

Panel A) This graph shows the ROC curve for the error rates for prosody word ID task with an area under the ROC curve = 0.78. Panel B) This graph shows the ROC curve for the error rates for prosody monosyllabic ID task with an area under the ROC curve = 0.78. Panel C) This graph shows the ROC curve for the stimulus-centered neglect measure with an area under the ROC curve = 0.55. Panel D) This graph shows the ROC curve for the viewer-centered neglect measure with an area under the ROC curve = 0.55.

NIHSS who were not detected with the prosody summary score; analysis shows that RHS patients have a higher probability of one had a subcortical infarct and one had an in infarct in the showing significant impairment in processing emotional prosody motor strip. Therefore, the most effective classification of right than showing significant neglect or extinction. The overall hemisphere stroke patients versus controls was with the NIHSS Prosody Score could classify 78.9% of patients vs. controls. In score combined with the Prosody Score, yielding an AUC of 0.89 contrast, the SCORE Neglect tests could classify only 55.8% of (CI 0.81-0.98). Together, they classified 82.7% of patients. Table patients vs. controls, and NIHSS neglect/extinction could classify 2Discussion summarizes the sensitivity and specificity of each test. 63.5 of patients vs controls. The SCORE neglect tests detected three additional stroke patients beyond those detected by NIHSS neglect test, but two of those three were also detected by the The current study investigated whether deficits in emotional NIHSS extinction test. NIHSS extinction identified 7 participants prosody comprehension are more sensitive than neglect for with extinction, but one of these was a control. Still, NIHSS neglect identifying acute stroke in the right hemisphere. The ROC plus extinction was slightly better in detecting right hemisphere J Neurol Transl Neurosci 2(1): 1037 (2014) 4/7 Hillis et al. (2014) Email: [email protected] Central

Table 2:

Comparison of sensitivity and specificity of SCORE Neglect, % Correctly NIHSS,Test and Prosody tests. Sensitivity Specificity classified

SCORE Neglect Test 14.30% 100.00% 55.80% Figure 1 Lesions overlay of the RHS patients.

NIHSS Extinction 17.90% 95.80% 53.90% An overlay of the lesions of the NIHSS Neglect+Extinction 35.70% 95.80% 63.50% 28 patients with the right hemisphere stroke (RHS). Nine slices are presented with all strokes from all the patients overlaid. Total NIHSS Score 75.00% 87.50% 80.80% Abbreviations:Prosody 92.90% 62.50% 78.90% SCORE: Stroke Cognitive Outcome and Recovery; NIHSS: along with more traditional tests such as line bisection, line National Institutes of Health Stroke Scale cancellation, reading, clock drawing, and have found that these two tests identified virtually all patients with neglect [34]. stroke than the SCORE neglect tests alone (without extinction). An alternative account of the rare neglect in RHS patients in Nevertheless, testing prosody detected 15 more patients with our study is the relatively3 small lesions (0.2 cc to 98.8 cc range; right hemisphere stroke than the NIHSS neglect plus extinction. mean = 53.79 cm ). Severity of extinction and neglect correlates The two prosody subtests took minimally more time (5.4-7.6 with the volume of infarct [35] and volume of hypoperfusion [36] minutes) compared to neglect subtests (2.9-5.8 minutes) and in acute stroke. Moreover, the patients were relatively young slightly more equipment. Although we presented the audiofiles compared to some previous studies (range= 33-75; mean=55.25 on a laptop, they could as easily be presented from a smart phone, years), although the age was average age of stroke patients for i-pod, or other electronic storage device. We have also presented our hospital. Previous studies have shown that neglect is more the response alternatives on either paper or laptop. The neglect common and more severe after right hemisphere stroke in older tests were “paper and pencil” tests, but laptop versions could be individuals [37,38]. Therefore, spared performance of many of created, particularly for the gap detection test. our RHS patients on neglect tasks suggests that either [1] the Cancellere and Kertsez, 1990 proposed that impairments spatial attention network is intact in the majority of our patients, in recognition of emotions from prosodic cues in patients with or [2] hemispatial neglect requires “two hits”: damage to one right hemisphere lesions may be due to attentional difficulties component of the spatial attention work, and damage to a more [12]. The current study does not provide clear support for this general attentional system for vigilance. This latter hypothesis hypothesis. In spite of spared performance on neglect tasks, is consistent with the model of Corbetta and Schulman [39], many RHS patients were profoundly impaired on the prosody which accounts for neglect in large right MCA strokes as damage tasks. Our study indicates that neglect (one type of spatial to both the bilateral dorsal spatial attention network and the attention) and emotional prosody impairment are independent right-dominant, nonspatial ventral attention network. It may deficits caused by a stroke in the right hemisphere. There is be that comprehension of emotional prosody is a better marker other evidence that RHS patients have significant difficulty in of right hemisphere stroke than neglect in unselected, diverse comprehension of emotions from prosody without visual neglect stroke patients (many of whom have small strokes, and now have [13]. However, such findings do not rule out that other types of average age of 55), while neglect remains a strong marker of large attentional deficits may underlie both prosodic impairments and right MCA stroke. The important point is that neglect is not the neglect. only cortical function that is impaired after RHS. The addition of test of other right hemisphere cortical functions, such as prosody, Some brain regions have been identified that can result in Conwouldclu improvesion detection of RHS. both emotional prosody comprehension impairment and neglect. Using multivariate pattern analysis of activation during a gender recognition task during event-related functional MRI of young The important finding of our study is that impairments in healthy adults, Ethofer and colleagues [2009] observed that comprehension of emotional prosody is a common indicator of each emotion category had a different localization of activation. acute right hemisphere dysfunction – even more common than However, all emotion categories activated voxels in bilateral mid hemispatial neglect or extinction in some populations. These superior temporal gyrus (STG; (25), implicating the role of mid results indicate that acute stroke assessment could be improved STG in processing prosodic features irrespective of the emotion by including a test (perhaps a downloadable audio file for a category. Right STG has been associated with left USN [1,26-28] mobile phone) of prosodic comprehension. Furthermore, the or at least left stimulus-centered neglect [29]. Several studies addition of evaluation of prosody comprehension may improve have implicated the right inferior frontal gyrus in evaluative our measures of effectiveness of interventions to salvage right judgments of emotional prosody [30,31] and inferior frontal lobe cortical function, such as reperfusion therapies. However, in neglect tasks [32,33]. Patients in our study as well had lesions the effectiveness, reliability, and efficiency of testing prosody in frontal, temporal and parietal regions. An overlay of lesions of comprehension at bedside (e. g. in an Emergency Department all the patients is shown in Figure 2. setting, which might require headphones) would need to be One account of the rare neglect in RHS patients in this study testedAckno in awl muched largergem studyents with an independent population. is that we might not have used adequately sensitive tests of USN. However, the NIHSS also demonstrated that only 18% patients had neglect. Additionally, we have previously used these tests This work was supported by: National Institute of Neurological J Neurol Transl Neurosci 2(1): 1037 (2014) 5/7 Hillis et al. (2014) Email: [email protected] Central

Ro

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38. evine DN. Unilateral neglect is more severe and common in older 39. Corbetta M, Shulman GL. Spatial neglect and attention networks. Annu patients with right hemispheric stroke. Neurology. 2009; 73: 489. Rev Neurosci. 2011; 34: 569-599.

Cite this article Dara C, Bang J, Gottesman RF, Hillis AE (2014) Right Hemisphere Dysfunction is Better Predicted by Emotional Prosody Impairments as Compared to Neglect. J Neurol Transl Neurosci 2(1): 1037.

J Neurol Transl Neurosci 2(1): 1037 (2014) 7/7 Central Journal of Neurology & Translational Neuroscience Special Edition on Cerebrovascular Disease Elisabeth B. Marsh* and Rafael H. Llinas Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Edited by: Elisabeth B. Marsh Rafael H. Llinas Department of Neurology Department of Neurology The Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine Baltimore, MD, USA Baltimore, MD, USA

Diagnosis/Management Considerations Common risk factors for stroke have been well studied; however, the more uncommon etiologies and medical effects of stroke are only now becoming clear. The first paper is a nice description of mechanical compression of a major artery resulting in continued embolization. This mechanism would not have been diagnosed without careful thought and imaging. It reminds us of the importance of a complete evaluation and expanded differential, particularly in those without the “typical” vascular risk factors. Hypercoaguable states secondary to cancer represent another area deserving of discussion. Cryptogenic stroke is a universally frustrating problem. Dearborn and colleagues detail one institution’s approach to these patients. A majority of the morbidity and mortality in stroke has been reduced by simple interventions: prevention of aspiration pneumonia, fever, and deep . Prior to implementation of these measures, it was not uncommon for a relatively small stroke to result in death from medical complications. The last paper highlights a more rare, but equally devastating medical complication of both anterior and posterior circulation strokes, whose prevention strategies may be different due to different underlying etiologies. Central Journal of Neurology & Translational Neuroscience

Case Report Special Issue on Position Dependent Carotid Cerebrovascular Disease Corresponding author Carolyn A. Cronin, University of Maryland School of Impingement Causing Recurrent Medicine, 110 South Paca Street, Baltimore, MD 21201, Tel: 410-328-3871; Fax: 410-328-5899; E-mail: Strokes Submitted: 25 November 2013 Carolyn A. Cronin1*, Manuel Fortes2 and Teng C. Lee3 Accepted: 20 January 2014 1Department of Neurology, University of Maryland School of Medicine, Baltimore MD, USA Published: 28 January 2014 2 Department of Radiology, University of Maryland School of Medicine, Baltimore MD, USA Copyright 3Department of Surgery, University of Maryland School of Medicine, Baltimore MD, USA © 2014 Cronin et al.

Abstract OPEN ACCESS

We report the case of a young man with recurrent strokes over a four year period, Keywords all occurring after leaning forward. He had suffered damage to the right subclavian • Stroke and right carotid in a car accident 20 years prior. Review of history and • Stroke in Young Adults imaging concluded that all of his infarcts had been in the distribution of the right carotid artery. CT angiogram revealed that a segment at the origin of the right common carotid artery was adjacent to the sternum and kinked at the point of contact. Proposed mechanism of infarcts is position dependent intermittent vessel damage causing thrombosis and distal embolization. The patient underwent surgical repair, with no further events. This case highlights the importance of evaluating structures adjacent to vessels in patients with cryptogenic strokes.

Abbreviations problems, and was found to have a right occipital intracerebral hemorrhage. Anticoagulation was stopped and he was discharged MRI: Magnetic Resonance Imaging; MRA: Magnetic on clopidogrel. Resonance Angiogram; CT: Computed Tomography; MCA: Middle Cerebral Artery; PCA: Posterior Cerebral Artery; TIAs: Transient After that admission, he developed migrainous headaches Ischemic Attacks. consisting of pain on the right side of his face, head, and eye in

Case Presentation recurrent episodes of the “head rush” feeling after leaning association with flashing lights in the right eye. He also noticed A 39 year old man came to Neurology clinic for a second forward. These were sometimes followed by transient feelings of opinion. His general health status was good, with none of the warmth and paresthesias on his right face. common stroke risk factors. At age 19, he had been in a car crash Eight months later, he developed frequent episodes of with trauma to the chest requiring surgery to repair damage to lightheadedness and tingling in his right arm after actively using the aorta, right subclavian, and right common carotid arteries. the arm. He was found to have right subclavian stenosis and He recovered well, with no symptoms until age 36 when he had subsequently underwent axillo-axillary bypass. The right arm symptoms and lightheadedness resolved, but the migraines and yard work, he developed a “head rush” feeling followed by visual “head rush” episodes persisted. problems,his first stroke. dysarthria, Upon straighteningleft facial droop up afterand left leaning hand over numbness. during Most of the symptoms resolved in a couple days, with residual Six months later, he had another episode of dizziness and left upper quadrantanopsia. An angiogram showed left hand numbness after bending over. MRI revealed a right in the right carotid bulb, for which he underwent carotid cortical stroke, and evaluation with MRA head and neck, EEG, endarterectomy. He was discharged on warfarin, aspirin, and echocardiogram, and hypercoagulable labs was unremarkable. atorvastatin. Four months later, he had an episode while leaning over to shovel

Six months later, he had another episode of left hand weakness, dysarthria, and confusion. MRI showed multiple small numbness after bending forward. His anticoagulation was infarctssnow of head in the rush right followed MCA andby flushing PCA territories. of his right Hisface, symptoms left sided subtherapeutic, and MRI was positive for right cortical stroke. improved to residual left hand weakness only. Symptoms resolved after about a week. Four months later he was admitted for a transient episode of “head rush” after bending over, At this point, he presented to our clinic for further evaluation. was again found to be subtherapeutic on warfarin, and placed on Based on his history and prior imaging, all of his strokes and TIAs heparin IV. The following day, he complained of increased vision appeared to be in the distribution of the right internal carotid

Cite this article: Cronin CA, Fortes M, Lee TC (2014) Position Dependent Carotid Impingement Causing Recurrent Strokes. J Neurol Transl Neurosci 2(1): 1038. Cronin et al. (2014) Email: [email protected] Central artery (including the occipital infarcts, secondary to a large right posterior communicating artery and diminutive P1 segment carotid artery was then transected and anastomosed to the graft. of the right posterior cerebral artery). To better evaluate his TheUK) previouswas anastomosed aorto-carotid to the graft ascending was freed aorta. from The the right manubrium common vasculature, a CT angiogram was performed. Initial report was posteriorly, transected as proximally as possible to its origin from of patent vessels throughout. Careful attention to the origin of the aorta, and removed. The previous axillo-axillary bypass graft the right common carotid artery showed that the vessel was in was then transected and anastomosed to the free end of the new contact with the sternum, with a kink in the vessel at the area bifurcated graft, and the remainder of the previous axillo-axillary of contact (Figure 1). Bending forward could put additional graft was resected and removed. A Doppler device was used to pressure on the vessel in this location, causing vessel injury, with subsequent thrombus formation and artery to artery the right axillary artery, and the chest was closed. embolization. It could also cause transient hypoperfusion leading confirm good flow in both the right common carotid artery and The patient was kept on dual antiplatelet agents (Plavix 75mg to the head rush sensations, with warmth and paresthesias on daily and aspirin 81mg daily) for 3 months and then switched to 81 mg aspirin alone. He recovered well from the surgery and the external carotid artery. the right side of the face likely a result of changes in blood flow in reported no further episodes of focal symptoms or head rush. His migraine headaches also resolved post-operatively. were discussed with the patient, and the decision made to proceedThe imagingwith surgical findings reconstruction. and proposed mechanism of strokes Discussion Boney abnormalities causing vessel damage are a rare but Surgical Description important cause of stroke, as the underlying lesion may be The axillo-axillary bypass graft previously placed across amenable to surgical correction. One of the authors has previously the midline was dissected out, and extensive adhesiolysis was reported a case in which a congenital boney abnormality of performed to free the heart from the anterior chest wall, and to the occiput was found to be causing recurrent vertebral artery dissect out the ascending aorta. The previous aorto-to-carotid damage and strokes [1]. Cerebral can also be seen and aorto-to-subclavian bypass grafts were avoided to prevent with damage to the subclavian artery from a cervical rib in the embolization of debris within them. The ascending aorta was thoracic outlet syndrome [2]. Typically, the carotid artery is not then clamped with a partial occluding clamp and an opening made in a position where it can be damaged by surrounding structures, about 3 cm above the aortic valve. The proximal end of a custom- although an intriguing association has been found between designed bifurcated Dacron graft (Terumo, Vascutek, Scotland, styloid process length and carotid [3]. In this case, the prior injury and reconstruction brought the carotid into an unusual position relative to the sternum. This case demonstrates that careful review of not just the vessel lumen, but also the surrounding structures can sometimes reveal a cause of stroke. CT angiogram is an imaging modality that allows for excellent visualization of both vessels and surrounding boney structures. 3-dimensional reconstruction programs that allow for rotation of the image and viewing from alternative angles can sometimes reveal lesions that are not immediately apparent in standard imaging protocols. References 1. recurrent posterior circulation strokes. Stroke. 2011; 42: e370-2. Figure 1 Imaging of the right common carotid artery origin. Cronin CA, Aldrich EF, Kittner SJ. Occipital bone abnormality causing A. Pre-operative CT angiogram, Arrow shows likely location of position- 2. dependent carotid origin impingement subclavian artery: a source of cerebral embolism. Neurology. 2009; B. Post-operative CT angiogram 73:Gooneratne e11-2. IK, Gamage R, Gunarathne KS. Pearls & oy-sters: distal *Connection to right common carotid artery. ^Connection to right axillary artery 3. (pre-op this is an axillo-axillary bypass, post-op this is an aorto-axillary graft). carotid artery dissection is associated with styloid process length. Neurology.Raser JM, Mullen2011; 77:MT, 2061-0266. Kasner SE, Cucchiara BL, Messé SR. Cervical

Cite this article Cronin CA, Fortes M, Lee TC (2014) Position Dependent Carotid Impingement Causing Recurrent Strokes. J Neurol Transl Neurosci 2(1): 1038.

J Neurol Transl Neurosci 2(1): 1038 (2014) 2/2 Central Journal of Neurology & Translational Neuroscience

Review Article Special Issue on Stroke and Cancer- A Cerebrovascular Disease Corresponding author Jennifer L. Dearborn, Department of Neurology, the Complicated Relationship Johns Hopkins Hospital, Phipps 4th floor, 600 N Wolfe St, Jennifer L. Dearborn*, Victor C. Urrutia, and Steven R. Zeiler Baltimore, MD 21287, Tel: 410-955-6626; Fax: 410-614- 1008; E-mail: Department of Neurology, Johns Hopkins Hospital, Baltimore MD Submitted: 25 November 2013 Accepted: 20 January 2014 Abstract Published: 28 January 2014 The interrelationship between stroke and cancer is complex. Cancer and stroke Copyright may occur independently in a given patient, or cancer may directly or indirectly lead © 2014 Dearborn et al. to stroke via: hypercoaguability, non-bacterial thrombotic endocarditis (NBTE), direct tumor compression of blood vessels, or treatment-related effects which potentiate OPEN ACCESS stroke. Patients with cryptogenic stroke are relatively common, and under the right circumstances, may provide an opportunity to screen for occult malignancy. In this Keywords review, we discuss relevant data linking stroke and cancer as well as propose a • Stroke testable algorithm for cancer screening in the patient with cryptogenic stroke. Future • Cancer directions should focus on validating patient-care algorithms in prospective clinical • Hypercoagulable States trials to provide an evidence base for this important issue. • Venous Thromboemoblism • Non- Bacterial Thrombotic Endocarditis

Introduction compared to patients without cancer who were admitted to a Cancer and ischemic stroke independently carry a large burden of morbidity and mortality as the second and fourth leading cause of death in the United States [1]. They each represent an investigation,stroke unit [13]. is Nevertheless, more common the in classification stroke patients of “cryptogenic” with cancer, enormous expenditure as a percentage of health care resources, [10]stroke, suggesting meaning an that association no cause between was identified malignancy despite and unknown detailed manifested by lost productivity and disrupted family structures mechanisms leading to stroke. Of note, 67% of strokes in cancer due to death and dependency. Cancer patients frequently have patients appear as multiple embolic events on imaging in one study strokes, both from traditional risk factors and from mechanisms [14] suggesting that clot formation and embolization may often thought unique to malignancy. An autopsy study of patients with be the culprit. Although cancer can co-exist and even accelerate known cancer at time of death showed 15% of patients suffer traditional cerebrovascular risk factors, we hypothesize that in from stroke diagnosed pathologically; [2] however only half of a certain subset of patients, cancer causes stroke more directly. these strokes were noted during life. In addition, patients with Multiple mechanisms, supported by multiple lines of evidence, venous thromboembolism are more likely to be diagnosed with may link stroke with cancer. We explore each below. Findings are cancer in the ensuing years, suggesting that hypercoaguability summarized in Table 1. with stroke and cancer have poorer clinical outcomes and longer Hypercoagulability hospitalmay be anstays important compared first with presentation stroke patients in cancer without [3]. cancer Patients [4]. Unfortunately, detection, prevention, and treatment of stroke by which cancer can cause stroke is via abnormal coagulation in cancer patients have been largely understudied. In addition, Perhaps the most important and underreported mechanism clinicians in many stroke centers must grapple with the fairly in 1865, referred to migratory in a patient high rate of embolic-appearing stroke where no etiology is found. withcascades. a visceral The eponymous carcinoma, Trousseau’s [15] but hassyndrome, since been first described expanded This rate of cryptogenic stroke has been quoted as high as 26-40 to describe any hypercoagulable state associated with cancer % of patients [5-8]. It is tempting to consider hypercoagulability [16]. Coagulation disorders, such as disseminated intravascular from a previously undiagnosed cancer as a possible etiology coagulation (DIC), are more likely to be seen in stroke patients in such patients [4,9]. In this review, we will focus on the data with cancer than without [4,11,12]. Cancer patients with linking cancer as a possible etiology of stroke as well as suggest cryptogenic stroke were found to have elevated D-Dimer levels possible diagnostic and management schemes. compared to stroke patients without malignancy [9]. Background Although many malignancies have been associated with The most frequent causes of stroke in cancer patients are hypercoagulability, adenocarcinoma is frequently linked with traditional cerebrovascular risk factors such as hypertension, clotting disorders as well as malignancy-associated stroke and, n and tobacco use [10- therefore, bears special consideration. In Japan, the incidence of colorectal cancer has been reported to be 16 per 10,000 person- hyperlipidemia, diabetes, atrial fibrillatio 12]. Vascular risk profiles of cancer patients are similar when Cite this article: Dearborn JL, Urrutia VC, Zeiler SR (2014) Stroke and Cancer- A Complicated Relationship. J Neurol Transl Neurosci 2(1): 1039. Dearborn et al. (2014) Email: Central

Table 1: Cancer Related Mechanisms of Stroke. Mechanism Causal factor Associated tumors Stroke Characteristics Adenocarcinoma of breast, lung, Adenocarcinomas especially; secrete mucin; prostate, etc. Hypercoagulability tumors activate coagulation cascade; Also brain, or infarcts, end vessels release pro-coagulant cytokines hematologic malignancies Embolic appearing Uncertain, likely similar to Venous-to-arterial embolism tumors of hypercoagulable state Multiple widely PFO,Sterile right-to-left vegetations, shunt clumps of platelets and Adenocarcinoma is most Embolic appearing Non bacterial thrombotic endocarditis distributed small and common large strokes fibrinTumor develop growth on and aortic resultant valve edema Glioblastoma multiforme, Direct tumor compression of vessel metastasis to brain common Rare- cardiac tumor causes embolization of Atrial or aortic valve myxoma, Large vessel, MCA Tumor embolism compressesmalignant cells major intracranial vessel metastatic tumors to heart Embolic appearing myeloma, Waldenstrom’s Hyperviscocity hypoviscious obstruction of small end Small end-vessels strokes Macroglobulinemia,Polycythemia vera, multiple vesselsRare-“Thickened” blood causes leptomeningeal carcinomatosis

Multiple vascular Angioinvasive/infiltrative wall, causing irregularities that territory infarcts predisposeRare-Hematologic to arterial malignancies embolism infiltrate Radiation after head and neck cancer B-cell lymphoma causes vasculopathy leading to accelerated Squamous cell carcinoma, other Post –radiation vasculopathy , predisposing to vessel wall head and neck tumors affected carotid irregularities and embolism Embolic stroke from the Associated with as cisplatin, Chemotherapy associated Unknown Varied thalidomide, lenalidomide, and bevacizumabmethotrexate, L-aspariginase, years for the general population; however, the incidence was found to be nearly 500 times in patients presenting initially with stroke [17]. Mechanistically, adenocarcinomas are thought to inProtein cancer C patients,activation likely thus from decreasing multiple a natural mechanisms “brake” of on locally the potentiate thrombi via production of mucin, a high molecular releasedanticoagulation cytokines system and secreted[20]. Platelet proteins activation by tumor is also and increased elevated levels of von-Willebrand factor [20]. normally by endothelial cells. Adenocarcinomas especially of Venous-to-arterial embolism theweight pancreas, “sticky” colon, molecule breast, lung, that prostate, is glycosylated and ovary and can secreted secrete this molecule directly into the bloodstream, precipitating a viscous, and hypercoagulable state [15,18]. Mucin can interact of hypercoagulability is deep and/or with certain cell adhesion molecules (CAM), on endothelial cells, pulmonaryPerhaps embolus. the most These well venous recognized clots may clinical lead to presentation stroke via platelets, and lymphocytes to induce the formation of platelet a direct venous-to-arterial shunting – sometimes referred to as rich microthrombi.

Further, tumor cells can release pro-coagulant molecules “paradoxical” emboli. There is debate about whether venous to directly, the most well know of which are tissue factor (TF) and doubled,arterial thrombo-embolization suggesting that something via a patent about foramen the shunt ovale increases (PFO) occurs. The likelihood of having a stroke in patients with PFO is factor VII to potentiate the coagulation cascade, and thereby the degree of venous-to-arterial shunting correlated with risk of thrombosis.cancer pro-coagulant TF has been (CP) found [19,20]. in symptomaticTF is a protein atherosclerotic that binds to stroke recurrencerisk [25]. On [26]. the otherOne interesting hand, neither study the found size ofan the increased PFO or plaques in carotid stenosis, prompting the hypothesis that TF rate of pelvic thrombosis in patients with cryptogenic stroke, cancers (81% in one sample assay), and is known to be a cysteine proteinasedestabilizes which plaque directly [21,22]. cleaves CP is released factor X by to the Xa, majority ultimately of clotssome increases of whom thehad risk a PFO, of paradoxicalsuggesting a embolization possible mechanism [28]. [27]. Nevertheless, it seems reasonable that increased risk of venous Nonbacterial thrombotic endocarditis resultingTumor-endothelial in the generation reactions of thrombin are [23,24]. important for release of local chemical mediators. Malignant cells release pro- Another common mechanism relating stroke and cancer sloughing of vascular endothelial cells as well as increased coagulant cytokines such as TNF-alpha, IL-1 and IL-6, causing developis nonbacterial on the cardiac thrombotic valves, endocarditisin descending (NBTE),order of frequency: previously monocytes, and cancer cells to express TF, thereby potentiating aortic,known mitral, as marantic and a combination endocarditis. of In aortic NBTE, and sterile mitral vegetations [29]. The theblood clotting sludging cascade [23,24]. [24]. These In cytokines addition, induce these cytokinesendothelial inhibit cells,

mechanism is thought to arise from disrupted fibrin attaching to J Neurol Transl Neurosci 2(1): 1039 (2014) 2/9 Dearborn et al. (2014) Email: Central

Regardless of the underlying pathophysiology, the changes can a network onto which platelets can adhere. Transesophageal previously undamaged valves in high flow areas and developing netlikelead to radiological vessels and findings transdural similar anastomosis to Moyamoya distal syndrome. to the echocardiography (TEE) is thought to be more sensitive that Patients develop stenosis of the carotid vessel with abnormal workup.transthoracic In a retrospective echocardiography study (TTE) 8 of 24 in patients detecting with valvular cancer vegetations [30]. Often a TEE is not part of a standard stroke breaststenosis radiation [54]. Head therapy and neckwhere radiation neck exposure therapy is (HNXRT)minimal [55]. may Squamousalmost double cell the carcinoma risk of stroke, is the with most the common exception cancer of adjuvant treated were found to have NBTE, [4] which is frequently associated with adenocarcinoma [31]. Systemic emboli occur in nearly 50% of times higher in the radiation therapy cohort than the reference uniformlypatients with found NBTE, to with have cerebral multiple emboli widely being distributed quite common small cohortusing HNXRT. [56]. In one analysis, the overall rate of stroke was 1.44 and[29,32]. large The strokes, diffusion whereas MRI pattern those with in patients bacterial with endocarditis NBTE was Some chemotherapeutic agents have also been associated with had more varied stroke patterns, sometimes involving a single an increased risk of stroke, such as cisplatin, methotrexate and vascularDirect tumor distribution effects [33]. [57,58]. They are thought to be related to thromboembolic events L-aspariginase, however the mechanisms are poorly understood Direct tumor effects, either from tumor compression, or from associated with cerebral venous thrombosis in children treated (both venous and arterial). For example, L-aspariginase has been Metastases to the brain, as well as primary brain tumors, can tumor embolism are another cancer specific mechanism of stroke. lenalidomide have been associated with stroke [59-61] and are cause direct compression of blood vessels, either by direct tumor for leukemia [36]. The antiangiogenic agents thalidomide and ischemia and subsequent infarction in the territory distal to the associated with a high risk of VTE [62,63]. invasion or via tumor bed edema, [34-36] leading to cerebral is used in a variety of cancer types including glioblastoma differentiate from tumor progression alone. It bears special Bevacizumab, a monoclonal antibody against VEG-F receptors mentionaffected vessel.that direct This tumor presentation effects can can also be difficultlead to hemorrhagic to clinically arterial thrombotic event rate, [62] however pooled analysis did stroke within the cranial vault. Hemorrhagic conversion of multiforme and other solid tumors. It is associated with a 3% brain metastasis is a relatively rare occurrence in a population tumors, including breast, colon and non-small cell lung cancer, of non-hypertensive hemorrhagic strokes (1 to 10% of cases) bevacizumabnot show an increased plus chemotherapy, risk of VTE compared [64,65]. In with treatment chemotherapy of solid alone, has a hazard ratio of 2.0 for arterial thrombotic events some examples of tumor types with a tendency for hemorrhagic [65]. A retrospective analysis of the cohort with glioblastoma [37]. Melanoma, renal cell carcinoma, and choriocarcinoma are multiforme in treatment trials for bevacizumab showed a related to of tumor beds, which are rich in vasculature. stroke rate of 1.9%, and a hemorrhagic stroke rate of 1.9%. conversion based on case studies [37,38]. The mechanism is likely The attributable risk from the drug rather than malignancy or Other rare causes of direct cancer effects leading to stroke traditional risk factors is unclear [66]. Tumors that are most likely to affect the heart include melanoma, Screening for cancer in the patient with cryptogenic whichinclude has embolism a high torate the of brain hematologic from metastasis spread, in carcinomas the heart [39-41]. of the stroke lung, breast, esophagus or hematologic malignancies, although The data suggests that cancer is either directly or indirectly responsible for stroke in a certain subset of patients (as opposed tumors, such as atrial myxomas, although benign also have embolicmany tumor potential, types have [42,44] been and reported hematologic [42,43]. malignancies Primary cardiac can should consider screening for occult cancer in a subset of result in strokes by directly affecting intracranial structures cryptogenicto just coexistent stroke with patients. vascular However, risk factors). the subsetAs such, of clinicians patients requiring stroke-prompted cancer screening, the optimal diagnostic approach, and how the approach should differ based polycythemiaand/or blood vera, flow. can Hyperviscous lead to decreased obstruction perfusion of end and vesselsstroke upon age, clinical presentation, and associated risk factors, [45,46].from the Intravascular malignant lymphomatosis, hematologic cells, also known as exemplified as angiotropic by has yet to be determined. Using existing data, we suggest an approach that may help to diagnose occult cancer as well as origin and can cause multiple territory cerebral infarcts by an lymphoma or neoplastic angioendotheliosis, is primarily of B-cell provide testable hypotheses for future improvement of this methodology in stroke patients with cryptogenic stroke (Figure 1). We focus on diagnostics associated with occult cancer- elusiveinfiltrative diagnosis, process. as Othermuch organsof the testing are typically for systemic spared, disease although can induced hypercoaguability, since other causes of cancer-induced beskin negative. involvement is not uncommon [36,47,48]. This is often an stroke (e. g. direct tumor effects and treatment effects) are often Cancer-associated treatments and stroke apparent. Radiation treatment effect causes stroke by unique mechanisms [49]. Head and neck radiation causes a vasculopathy of medium and large sized vessels that often presents years after promptedOur approach cancer screening, assumes that as the patients cause with of stroke an identifiable is already radiation exposure. This vasculopathy is not well characterized, evident.stroke etiology Our approach (e. g. atrial includes fibrillation) stroke patients do not of need all ages, stroke- as we freely admit that that the optimal age to screen for cancer in but may be associated with accelerated atherosclerosis [50-53]. J Neurol Transl Neurosci 2(1): 1039 (2014) 3/9 Dearborn et al. (2014) Email: Central

Figure 1 An approach for malignancy screening in patients with cryptogenic stroke. In this approach, every patient with an embolic appearing cryptogenic stroke

examination, or serum testing suspicious for malignancy should undergo further evaluation with imaging. (regardless of age), undergoes an expanded history, physical examination, and serological work-up (D-Dimer). Patients with one or more finding on history, physical cryptogenic stroke patients is not known: older stroke patients Treatment of cancer-related stroke are more likely to have cancer; [67] on the other hand, younger of stroke risk factors independent of cancer is of utmost thus prompting further investigation [68]. In the patient with cancer and stroke, identification stroke patients are more likely to have a cryptogenic classification We begin with imaging characteristics. Multiple embolic importance. “Classic” cerebrovascular risk factors (hypertension, events (involving the brain and/or other organs) or presence disease, and tobacco use) remain the leading etiologies of stroke hyperlipidemia, diabetes mellitus, atrial fibrillation, carotid not consider lacunar stroke to be related to cancer-associated and risk factor modification is therefore paramount. Atrial hypercoagulabilityof VTE, prompts a since more lacunar extensive stroke work-up. occurs Generally,through different we do of cancer in patients with embolic appearing strokes, and, fibrillation should still be considered over hypercoaguability mechanisms [69,70]. When a cryptogenic stroke appears proven need for anticoagulation (eg. , hypercoaguable state embolic, we expand the medical history to include symptoms if discovered, anticoagulation initiated. Patients without a unexplained fevers, weight loss, and malaise). This should also such as Factor V Leiden disorder, large vessel dissection, atrial suggestive of cancer (i. e. , the presence of “B” symptoms such as Managing hypertension, hyperlipidemia, and diabetes; offering include questioning for environmental exposures associated fibrillation, etc. ) should be started on an anti-platelet agent. with cancer incidence (e. g. smoking and carcinogen exposures). counseling; and encouraging medication adherence are essential. We perform a careful general physical examination including smoking cessation counseling; providing life-style modification consideration is given to the evaluation of serum markers (such stroke bear special consideration. We should note at the outset Patients with known cancer and probable cancer-related asa breast D-Dimer) or testicular known to exam correlate in the with appropriate the diagnosis setting. of cancer, Next, that there are no direct studies that address treatment of any of the presumed cancer-induced stroke mechanisms discussed above. which could help to raise or lower suspicion [71,72]. D-Dimer Of particular concern is prevention of hypercoaguability-induced has an unknown sensitivity as a screening tool, but elevation stroke. Available data suggest hypercoaguability-induced stroke in cancer patients with stroke is well documented [73-75]. The further workup: (1) contrast enhanced CT scanning of the chest, is a real entity, but difficult to diagnostically confirm or design a presence of one or more of these “red-flags” should prompt treatmentIt remains plan effectively to be seen acknowledging whether there the isrisks a roleand benefits. for anti- ensuring that the patient is up-to-date on age appropriate cancer platelets in the secondary prevention of cancer-related stroke abdomen, and pelvis (PET scanning is a viable alternative), (2) (adenocarcinoma or otherwise). More data exist with respect to high risk women (age >50 years, age >25 with family history) anticoagulation. One study measured the effect of anticoagulation (using unfractionated heparin, low molecular heparin, or [76]screening, Testicular and ultrasound(3) consideration is not an of effective trans-vaginal screen ultrasound for testicular in warfarin) on micro-embolism [78]. Transcranial Doppler (TCD) cancer in men [77].

J Neurol Transl Neurosci 2(1): 1039 (2014) 4/9 Dearborn et al. (2014) Email: Central was used in stroke patients with cancer to determine the embolic superior to warfarin, although the studies were often small and may not have been adequately powered [62]. A study evaluating into those with conventional stroke mechanism, and those with antithrombotic prophylaxis with nadroparin versus placebo did signal in the middle cerebral artery (MCA). Patients were divided include a subgroup analysis of patients with stroke [82]. Although were more commonly detected in patients with high D-Dimer levels.presumed Treatment hypercoagulability. with anticoagulation Embolic was signals also measured noted to decrease by TCD D-Dimer levels [78]. This correlation between embolic signal and numberthere was of a strokes reduced was rate too of strokesmall to in drawthe nadroparin concrete conclusions. group, (3 of D-Dimer level may suggest that anticoagulation has the potential The769 patients) newer oral versus anticoagulants placebo group dabigatran (3 of 381 (a patients) direct thrombin the total to attenuate cancer-induced hypercoaguability leading to stroke. inhibitor) and rivaroxiban (a direct factor Xa inhibitor), have Further, these data suggest that tracking D-Dimer levels may be a method to measure the risk of cancer-induced embolism and/or in cancer subgroups. effect of anticoagulation in these patients. proven effective in DVT treatment, [83] but remain to be studied prevention in patients with cancer, there is also inherent risk. anticoagulation is superior for the prevention of Though there may be benefit to anticoagulation for stroke hypercoaguability-inducedBased upon these limited stroke, we data, must if then we consider assume which that the rate of hemorrhage in ischemic stroke patients [84,85]. form of anticoagulation is most appropriate in cancer patients. DevelopingLarge clinical a methodtrials show for thatthe selectionsystemic anticoagulationof high-risk patients increases who

(D-Dimer), and radiographic characteristics (presence of prior canThere be is extrapolated data that lowto arterial molecular stroke weight is unclear. heparin The (LMWH) results stroke),may benefit may the be most the optimal using clinical approach (stroke to severity),deciding in serologic whom prevents VTE in cancer patients; however, whether the results for cancer patients used to guide which patients should be of trials with LMWH are summarized in Table 2. The CLOT to initiate therapy. In the VTE literature, there is a risk score thestudy dalteparin established group the at use six of months LMWH versus in patients those treated with cancer with score includes high-risk characteristics such as: type of cancer, warfarinand DVT. [79].The probability Similar results of recurrent were seen VTE with was tinzaparinmuch lower and in anticoagulated for primary prevention of DVT/VTE [86]. The

platelet count, leukocyte count, D-Dimer, body mass index (BMI) Tsemuloparinable 2: [80,81]. Enoxaparin has not been shown to be and P-selectin. P-selectin is an adhesion molecule on endothelial

Study Important StudiesType of ofVenous study ThromboembolismSubjects (VTE) and Cancer. Intervention Outcome

Randomized, double blind, days. All patients received ENOXACAN II88 planned curative open surgery placebo controlled Enoxaparin vs placebo for 21 detected by ultrasound for332 abdominal patients undergoing or pelvic cancer days. Reduced the incidence of VTE Dalteparinenoxaparin for for 5 first or 6 6 days to 10 Randomized, open-label CLOT79 followed by Dalteparin vs clinical trial (N=336 treatment, n=336 warfarin for 6 months Recurrent VTE lower in with no standard care) Patients with 84 patients with squamous major increase in bleeding Randomized placebo cancer and a DVT, PE or both Dalteparin vs placebo for 18 Dalteparin favorably improved Altinbas et al.89 cell lung carcinoma receiving controlled weeks survival chemotherapy Randomized placebo Dalteparin vs placebo for Dalteparin did not improve FAMOUS90 controlled malignancy one year survival 385 patients with advanced Randomized placebo MALT91 controlled trial metastatic(N=148 treatment, or locally n=154 advanced six weeks survival solidcontrol) tumors Patients with Nadroparin vs placebo for Nadroparin favorably improved

Randomized, open-label Tinazeparin vs warfarin for LITE80 clinical trial (N=100 treatment, 100 Tinazeparin3 month outcomes group were similar, at 540standard patients care) with Patients locally with 12 months VTE was reduced in the 3 months Safety analysis showed no advancedcancer and or a metastaticDVT, PE or both PROSPECT92 increase in bleeding in treatment pancreatic cancer undergoing group Phase IIb chemotherapy Enoxaparin vs placebo Reduced rate of stroke in Randomized, double blind nadroparin group, but only six PROTECHT82 metastatic(N=779 treatment or locally and advanced duration of chemotherapy placebo controlled total strokes occurred, also was solidn=387 cancer placebo) receiving patients with versusNadroparin 4 months vs placebo for increase in bleeding complications chemotherapy

placebo) Semuloparin vs placebo until Semuloparin reduced the risk Randomized, double blind SAVE-ONCO81 (N=1608 treatment, n=1604 chemotherapy regimen was placebo controlled or locally advanced cancer changed increased risk of bleeding receivingPatients with chemotherapy metastatic of VTE, without an apparent

J Neurol Transl Neurosci 2(1): 1039 (2014) 5/9 Dearborn et al. (2014) Email: Central cells and platelets that was independently shown to be a predictor chemotherapy and radiation also requires careful consideration whenLMWH deciding is still unclear how to and proceed requires with further cancer study. therapy Treatment post-stroke. with We suggest that patients with known cancer and cryptogenic, of cancer associated VTE [87]. An interdisciplinary team, including physician experts, therapists, multiple embolic events (involving the brain and/or other and social workers, is best equipped to deal with the treatment decisions that follow. group with predisposition to hypercoaguability. (Generally, we doorgans), not consider VTE, or lacunar the presence stroke to of be adenocarcinoma related to cancer-associated represent a References hypercoagulability since lacunar stroke occurs through different 1. http://www.cdc.gov/nchs/fastats/lcod.htm mechanisms. ) [69,70] If any of the above conditions are present, in the absence of another obvious cause for embolic stroke, 2.

Graus F, Rogers LR, Posner JB. Cerebrovascular complications in In a patient in whom we are uncertain about the contribution of patients with cancer. Medicine (Baltimore). 1985; 64: 16-35. patients are likely to benefit from anticoagulation with LMWH. 3. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. 4. the cancer, we will often perform a TEE to investigate for NBTE. If Lancet Oncol. 2005; 6: 401-410. presentation of systemic cancer. J Stroke Cerebrovasc Dis. 2008; 17: present, NBTE would bias towards anticoagulation with LMWH. 169-174.Taccone FS, Jeangette SM, Blecic SA. First-ever stroke as initial aThe DVT TEE was with present. bubble Anticoagulation study can also tell should us about likely the be presence continued of a PFO, which by itself would not require anticoagulation, unless 5. until the cancer is in remission, the patient cannot tolerate it, or a Risk factors, outcome, and treatment in subtypes of ischemic stroke: bleeding complication occurs. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, et al.

Conclusions/future directions 6. the German stroke data bank. Stroke. 2001; 32: 2559-2566.

Stroke and cancer are intertwined by virtue of their relatively toKolominsky-Rabas TOAST criteria: incidence, PL, Weber recurrence, M, Gefeller and long-term O, Neundoerfer survival inB, common occurrence within the general population. It cannot be Heuschmann PU. Epidemiology of ischemic stroke subtypes according stressed enough that cancer is not the most common etiology of stroke, and that even in patients with cancer; the traditional ischemic stroke subtypes: a population-based study. Stroke. 2001; 32: 7. 2735-2740. risk factors are most commonly the underlying cause. There DO. Ischemic stroke subtypes: a population-based study of incidence Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers increase one’s risk for stroke. These include: hypercoagulable are, however, cancer-specific mechanisms that may further 8. and risk factors. Stroke. 1999; 30: 2513-2516. chemotherapy related hypercoagulability or post radiation Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR, et states induced by tumor cells, NBTE, vessel compression, al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann 9. Uemura J, Kimura K, Sibazaki K, Inoue T, Iguchi Y, Yamashita S. Acute date, there are no clinical trials leading to guidelines for diagnosis Neurol. 1989; 25: 382-390. effects, hyperviscocity, or vessel infiltration by cancer cells. To stroke patients have occult malignancy more often than expected. Eur or treatment of these conditions. The DVT/VTE literature provides 10. Neurol. 2010; 64: 140-144. some insight into treatment of a subgroup of “hypercoagulable” stroke in cancer patients with and without conventional mechanisms: aKim multicenter SG, Hong study JM, Kim in Korea. HY, Lee Stroke. J, Chung 2010; PW, 41: Park 798-801. KY, et al. Ischemic stroke patients who may benefit from treatment from LMWH, but specificOccult stroke cancer prevention may be studies an important have yet to missed be performed. diagnosis in 11. cryptogenic stroke. There is little data to suggest what should cancer patients be considered a manifestation of hypercoagulability? be done to screen for malignancy in patients with cryptogenic Stroke.Chaturvedi 1994; S, 25:Ansell 1215-1218. J, Recht L. Should cerebral ischemic events in stroke. First steps may include: 1) identifying a subgroup of 12. Zhang YY, Cordato D, Shen Q, Sheng AZ, Hung WT, Chan DK. Risk factor, pattern, etiology and outcome in ischemic stroke patients with cancer: malignancy surveillance, and 2) subsequently carrying out this stroke patients who are most likely to benefit from aggressive a nested case-control study. Cerebrovasc Dis. 2007; 23: 181-187. allow for more rapid detection of potentially treatable cancers, andscreening may informas part of decisions the inpatient on treatment evaluation. for Early secondary screening stroke will 13. Stefan O, Vera N, Otto B, Heinz L, Wolfgang G. Stroke in cancer patients: 14. a risk factor analysis. J Neurooncol. 2009; 94: 221-226. prevention. Our suggested approach needs to be validated in patients with active malignancy using diffusion-weighted imaging. systematic studies to determine which patients require more CerebrovascHong CT, Tsai Dis. LK, 2009; Jeng 28: JS. 411-416. Patterns of acute cerebral infarcts in aggressive screening and what are the most accurate diagnostic 15.

Varki A. Trousseau’s syndrome: multiple definitions and multiple tests. Our approach also requires an analysis of the cost benefit 16. mechanisms. Blood. 2007; 110: 1723-1729. of such a workup, as admittedly only 3% of all strokes are manifestations of chronic disseminated coagulopathy in patients resource intensive and costly [17]. Sack GH Jr, Levin J, Bell WR. Trousseau’s syndrome and other attributable to cancer and many screening tests such at PET are with neoplasms: clinical, pathophysiologic, and therapeutic features. Finally, treatment of a patient with stroke in the setting of cancer is complex and requires careful integration from 17. Medicine (Baltimore). 1977; 56: 1-37. both neurologic and oncologic experts. Although existing data Kwon HM, Kang BS, Yoon BW. Stroke as the first manifestation of 18. concealed cancer. J Neurol Sci. 2007; 258: 80-83. versus anticoagulation with warfarin versus anticoagulation with suggests LMWH may be superior, the role for antiplatelet agents Chaturvedi P, Singh AP, Batra SK. Structure, evolution, and biology of the MUC4 mucin. FASEB J. 2008; 22: 966-981. J Neurol Transl Neurosci 2(1): 1039 (2014) 6/9 Dearborn et al. (2014) Email: Central

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Cite this article Dearborn JL, Urrutia VC, Zeiler SR (2014) Stroke and Cancer- A Complicated Relationship. J Neurol Transl Neurosci 2(1): 1039.

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Research Article Special Issue on Isolated Pulmonary Edema Cerebrovascular Disease Corresponding author John C. Probasco, Department of Neurology, Johns without Myocardial Stunning in Hopkins School of Medicine, 600 N. Wolfe St., Meyer Brainstem Strokes 6-113, Baltimore, MD 21287, USA, E-mail: Submitted: 10 January 2014 John C. Probasco1*, Tiffany Chang1, David Victor2 and Paul Accepted: 20 January 2014 Nyquist1 Published: 28 January 2014 1Department of Neurology, Johns Hopkins School of Medicine, USA Copyright 2Department of Medicine, Johns Hopkins School of Medicine, USA © 2014 Probasco et al.

OPEN ACCESS Abstract Introduction: Ischemic stroke has been associated with stunned myocardium and Keywords neurogenic pulmonary edema (NPE). We studied a population of patients with large • Ischemic stroke vessel brainstem ischemic stroke to see if there was an increased risk of pulmonary • Pulmonary edema edema associated with strokes in this region independent of myocardial stunning. • Myocardial stunning Hypothesis: Large vessel ischemic strokes of the brainstem are associated with neurogenic pulmonary edema and occur independently of myocardial stunning. Methods: This is a retrospective case control study of 1,278 patient admissions. Two hundred ten patients were identified with large vessel ischemic stroke or transient ischemic attack (mean age 65 years, 55% female, 50% black). Infarction locations included: brainstem (N=22), right middle cerebral artery involving the insula (N=38), left middle cerebral artery involving the insula (N=37), and transient ischemic attack (N=113). Multivariate logistic regression models for presence of echocardiographic wall motion abnormalities, QTc-interval prolongation, elevated serum troponin, and pulmonary edema were developed to examine the relative contribution of stroke location and markers of cardiopulmonary dysfunction to each respective outcome, controlling for patient characteristics. Results: Large vessel brainstem stroke was associated with pulmonary edema (adjusted OR 29.23, 95% CI 1.90-449.51) but not cardiac abnormalities. Large vessel left middle cerebral artery stroke was also associated with pulmonary edema (76.44, 6.93-843.54) as well as QTc-interval prolongation (4.55, 10.77-19.24). Large vessel right middle cerebral artery stroke was associated with pulmonary edema (10.88, 1.02-116.70) as well as elevated serum troponin (10.51, 1.71-64.82). Conclusion: In a retrospective case control study, large vessel brainstem stroke was associated with the development of pulmonary edema independent of cardiac abnormalities associated with myocardial stunning, suggesting a separate brainstem pathophysiologic mechanism which directly affects the lungs but not the heart.

Introduction are not fully understood. They are thought to involve sympathetic hyperactivity and possibly anatomic inhibition due to insular Over 790,000 strokes occur annually in the United States, cortical injury [6-8]. Localization of ischemic stroke to the insula making it the fourth leading cause of death and the leading and the parietal lobe has been associated with fatal arrhythmias cause of disability in people over the age of 65 [1]. Pulmonary in animal models and human studies [7-9]. and cardiac complications after stroke are common. The association of ischemic stroke with electrocardiographic change Respiratory failure occurs in 5-10% of patients with acute and elevated cardiac enzymes has been known for decades [2- ischemic stroke, most often secondary to aspiration and decreased airway protection. Pulmonary parenchymal disease stunning are transient left ventricular wall motion abnormalities, has been observed as a direct consequence of centrally mediated electrocardiographic4]. The classic triads abnormalities of findings and for elevation neurogenic in myocardial injury due to neurogenic pulmonary edema (NPE) [9,10]. NPE enzymes in the serum in the absence of coronary artery disease has been noted as a complication of a variety of neurological [5]. The physiological mechanisms underlying these associations syndromes, including basilar artery thrombosis and intracerebral

Cite this article: Probasco JC, Chang T, Victor D, Nyquist P (2014) Isolated Pulmonary Edema without Myocardial Stunning in Brainstem Strokes. J Neurol Transl Neurosci 2(1): 1040. Probasco et al. (2014) Email: Central hemorrhage [9-11]. The anterior and posterior cerebrovascular presence or absence of pulmonary edema was determined by distributions have both been implicated in NPE [9,11,12]. review of chest radiographs within 96 hours of admission, when available. These were reviewed by physician reviewers blinded It is unknown how often acute pulmonary edema noted in the to patient diagnosis and study hypothesis (T. C. and D. V. ) using setting of ischemic stroke occurs independently or as a result of previously established criteria [15]. cardiac dysfunction. It is also unknown if there is a relationship of particular cerebrovascular distributions to particular patterns Statistical Analysis of cardiac and/or pulmonary dysfunction in ischemic stroke. For continuous variables, medians with interquartile range Here we describe a retrospective review of patients treated at a tertiary stroke center for large vessel ischemic stroke, to explore For categorical variables, frequencies were measured. Group the association of the cerebrovascular distribution of infarction differences(IQR) and means for continuous with standard variables deviations were (SD) tested were by calculated. one-way to pulmonary edema and cardiac function derangements as analysis of variance with Bonferroni’s adjustment for multiple measured by electrocardiography, elevated cardiac enzymes comparisons. The 2 test for independence or Fisher’s exact test was used to examine group differences for categorical variables. an association between large vessel ischemia in the brainstem χ and echocardiography. pulmonary edema We occurring hypothesized independently that we would of cardiac find risk factors for development of pulmonary edema. Multivariate abnormalities associated with myocardial stunning. logisticUnivariate regression analyses analyses were performed were performed to assess with for outcomes significant of Patients and Methods interest (i.e. pulmonary edema, echocardiographic wall motion

A retrospective review was performed on all patients admitted interval prolongation) serving as the dependent variables. When or transferred to the cerebrovascular neurology service at Johns clinicalabnormalities, data was presence missing, of the elevated documented serum diagnosis troponin, wasand usedQTc- Hopkins Hospital from June 2009 through June 2011. Clinical based on clinical examination or report of clinical data at time of data obtained included: age; gender; race; and medical history admission. of diabetes, hypertension, hypercholesterolemia, smoking, For each multivariate logistic regression model, patient failure, diabetes and prior stroke or transient ischemic attack characteristics including age > 57 years [16], history of atrial (TIA).arrhythmia, Past medical atrial fibrillation,history was coronaryrecorded as artery per documentation disease, heart in the medical record at time of admission. mellitus, history of heart failure, history of hypertension, history offibrillation, smoking, history and stroke of coronary location artery were disease, included history as independent of diabetes All patients >17 years of age admitted to the Johns Hopkins variables and controlled for. In addition, diagnostic results Hospital cerebrovascular service were included, whether or indicative of cardiopulmonary dysfunction including presence not they died while admitted. Patients were included if they of wall motion abnormalities on echocardiogram, arrhythmia on had a discharge diagnosis of TIA (control group) [13]; ischemic stroke of the right or left middle cerebral artery (RMCA or pulmonary edema, and elevated serum troponin were included LMCA) ; or basilar artery ischemic stroke, stenosis or occlusion. andadmission controlled EKG, QTc for asprolongation independent on variablesadmission exceptEKG, presence when the of All other patients were excluded, including those who had dependent variable of interest for a respective multiple logistic ischemic strokes in multiple cerebrovascular distributions. To regression model. Collinearity diagnostics were performed to ensure inclusion of patients with large vessel middle cerebral assess for intercorrelations among independent variables. The artery infarction, of those patients with discharge diagnosis of amount of variation in the dependent variable explained by ischemic stroke of the RMCA or LMCA, only those patients with each respective model was assessed using Cox & Snell R Square cortex were included. To ensure inclusion of patients with large multivariate logistic regression model was assessed by Hosmer vesselradiographic brainstem findings infarctions, consistent of those with infarction patients with of the discharge insular and the Nagelkerke R Square tests. Goodness-of-fit of each diagnosis of basilar artery ischemic stroke, stenosis or occlusion, to respective logistic regression models were assessed using and Lemeshow’s test (H-L). Significance of regression coefficients within the midbrain, pons and/or medulla in the setting of basilar only those with radiographic findings consistent with infarction the p<0.05 level. All statistical analyses were performed using artery stenosis or occlusion were included. theWald’s SPSS test. (version Two-tailed 22, IBM, statistical Armonk, significanceNY) statistical was package assessed while at Imaging and laboratory data included: echocardiogram reports; electrocardiogram (EKG) reports upon admission Diego, CA) statistical package. figures were made using the Prism (version 5, GraphPad, San and 48 hours after admission; initial and peak serum troponin Results levels; chest radiographs during admission. Heart failure < 35% as measured Clinical characteristics by echocardiogram [14]. Cardiac wall motion abnormalities We completed a review of 1,278 patient records. There were werewas defined documented as an ejection by cardiologist-based fraction of interpretation of and included in our analysis. Of these patients, 55% were female, 50%210 patients were black, with 75%large hadvessel a history ischemic of stroke hypertension or TIA identified and their echocardiogram. Troponinemia was defined as >0.06 ng/mL, segment abnormalities and arrhythmias were determined from average age was 63.5 years (SD 15.9). Twenty-two patients had per institutional clinical laboratory designation. Nonspecific ST brainstem stroke in the setting of basilar occlusion or stenosis, 38 patients had large vessel right middle cerebral artery (RMCA) the final cardiologist report of EKG. Corrected QT (QTc) interval prolongation was defined as >460 ms per EKG report. The J Neurol Transl Neurosci 2(1): 1040 (2014) 2/7 Probasco et al. (2014) Email: Central strokes involving the insula, 37 patients had large vessel left Echocardiography middle cerebral artery (LMCA) strokes involving the insula, Echocardiograms were performed on 83 TIA, 35 RMCA, 31 LMCA and 14 brainstem stroke patients. There was no difference brainstem stroke group included two patients with isolated in proportion of patients with an ejection fraction < 35% ( 2 medullaryand 113 TIA infarct, control ten patientspatients werewith isolated identified. pontine The largeinfarct, vessel and (3, N=167) =3.93, p=0.27). Similarly, there was no difference ten with infarction of multiple brainstem structures. With the in proportion of patients with new diagnosis of heart failure orχ 2 (3,n=208) =14.75, decreased ejection fraction from baseline across groups ( 2 (3, p=0.002) and history of heart failure ( 2 (3,n=208) =10.72, N=167) =5.15, p=0.16). However, the proportion of patients p=0.01),exception patient of history groups of atrial were fibrillation similar in terms(χ of age; gender; with cardiac wall motion abnormalities on echocardiogramχ by race; history of prior stroke or TIA, diabetes,χ smoking and cardiologist interpretation varied across groups ( 2 (3, N=163) hypercholesterolemia (Table 1). =9.04, p=0.03) with a greater proportion of patients with RMCA χ Pulmonary evaluation stroke (0.34) than TIA (0.13) and brainstem stroke (0.07). There was no difference in proportions between the RMCA and LMCA Chest radiographs were available for review for 65 TIA, 28 (0.26) stroke groups. RMCA, 31 LMCA, 19 brainstem stroke patients. The presence of pulmonary edema was determined based on review of available The multivariate model for echocardiographic wall motion chest radiographs within 96 hours of admission [15]. For all other abnormalities explained between 31.4% and 45.8% of the variance patients, pulmonary edema assessment was based on pulmonary in having cardiac wall motion abnormalities on echocardiogram, examinations and available chest radiograph reports at time of correctly classifying 83.3% of cases, compared to baseline 2 admission. (8) =9.20, p=0.33) without evidence of intercorrelations among The proportion of patients with pulmonary edema varied prediction rate of 73.5%, and fit the observed data well (H-L χ 2 across the four groups ( (3, N=210) =52.02, p<0.0001, Figure. contribution to the model. Only patient history of heart failure 1A). A greater proportion of brainstem (0.50) and LMCA (0.43) (adjustedthe independent OR 9.63, variables. 95% CI Stroke 2.17-42.78) location and made patient no significant history of χ stroke patients had pulmonary edema compared to both the TIA coronary artery disease (8.44, 2.04-34.93) were predictive of control (0.02) and RMCA stroke (0.24) groups. the presence of wall motion abnormalities on echocardiogram Of the potential predictors for presence of pulmonary during admission. edema after large vessel ischemic stroke, only patient age Serum troponin > Serum troponin levels were measured for 65 TIA control of heart failure, stroke location and elevated serum troponin patients, 27 RMCA, 28 LMCA and 12 brainstem stroke patients were57 years, predictive patient (Table history 2). Theof atrial multivariate fibrillation, logistic patient regression history 2 (3, N=210) =20.43, model for presence of pulmonary edema explained between p<0.0001). A smaller proportion of TIA patients (0.05) had 36.7% and 53.5% of the variance in development of pulmonary andelevated varied serum significantly troponin acrosslevels than groups RMCA (χ (0.41), LMCA (0.32) edema, correctly classifying 81.4% of cases compared to baseline and brainstem (0.33) stroke patients. 2 (8) =5.50,p=0.70) without evidence of intercorrelations among The multivariate logistic regression model for presence of predictionthe independent rate of variables. 73.5%, and As fitshown the observedin Table 3,data having well a(H-L LMCA χ elevated serum troponin explained between 26.8% and 40.8% stroke (adjusted OR 76.44, 95% CI 6.93-843.54), a RMCA stroke of the variance in having an elevated serum troponin, correctly (10.88, 1.02-116.70) or a brainstem stroke (29.23, 1.90-449.51) classifying 84.3% of cases compared to baseline prediction rate was predictive of development of pulmonary edema. 2 (8) =4.71,p=0.79)

of 77.5%, while fitting the data well (H-L χ Table 1: Patient Characteristics. Means (SD) are presented for the continuous variable “age”, and N(%) presented for all other categorical variables. Group differences for continuous variables were tested by one-way analysis of variance with Bonferroni’s adjustment for multiple comparisons, with 2 test for independence was used to examine group differences for categorical variables with p-value presented. p-value presented. The χ TIA (N=113) R MCA (N=38) L MCA (N=37) Brainstem (N=22) Test Result Age 63 (23) 71 (24) 65 (33) 65 (12) p=0.87 Female Sex 70 (62%) 21 (55%) 15 (41%) 10 (46%) p=0.11 African American 57 (50%) 18 (47%) 16 (43%) 13 (59%) p=0.68 History of Stroke or TIA 46 (41%) 12 (32%) 9 (25%) 7 (32%) p=0.34 History Atrial Fibrillation 6 (5%) 10 (27%) 7 (19%) 2 (9%) p=0.002 History of Heart Failure 8 (7%) 9 (24%) 8 (22%) 2 (9%) p=0.01 History of Diabetes 30 (27%) 8 (22%) 9 (25%) 10 (46%) p=0.22 History of Hypertension 84 (74%) 28 (76%) 26 (70%) 20 (91%) p=0.33 History of Smoking 47 (42%) 18 (47%) 15 (41%) 11 (50%) p=0.82 History of 47 (42%) 13 (35%) 11 (31%) 12 (55%) p=0.29 Hypercholesterolemia

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Table 2: Univariate Analyses of Potential Predictors for Presence of Pulmonary Edema. 2 test for independence or Fisher’s exact test was used to examine group differences for categorical variables, with p-value presented. *designates those factors examined by Fisher’s exact test. History of hypercholesterolemia (p=0.65), ejection fraction of < 35% on echocardiogram (p=0.26), new The χ or worsened heart failure (p=0.29*), PR interval prolongation on initial electrocardiogram (0.33*), ST segment abnormality on initial electrocardiogram (p=0.77), and delayed R wave progression on

2 initialedema electrocardiogram (N=88, 83.8%) in the (p=0.57*) setting wereof normal not significant serum troponin predictors (N= 105) for the compared presence to on as pulmonaryseen in the settingedema. of **designates elevated serum that troponin significant (N=27). difference in proportions noted in performing χ test reflects difference in proportions of patients with pulmonary edema (N=17, 16.2%) and without pulmonary Pulmonary Edema Present Pulmonary Edema Not Present Test Result Patient Factors Age>57 (N=143) 31 (21.7%) 112 (78.3%) p=0.05 History Atrial Fibrillation (N=25) 10 (40.0%) 15 (60.0%) p=0.004* History of Coronary Artery Disease (N=41) 8 (19.5%) 33 (80.5%) p=0.75 Prior History of Heart Failure (N=27) 11 (40.7%) 16 (59.3%) p=0.002* History of Diabetes (N=57) 11 (19.3%) 46 (80.7%) p=0.73 History of Hypertension (N=158) 30 (19.0%) 128 (81.0%) p=0.39 History of Smoking (N=91) 15 (16.5%) 76 (83.5%) p=0.60 Stroke Location (TIA, RMCA, LMCA, Basilar) p<0.001 TIA (N=113) 2 (1.8%) 111 (98.2%) RMCA (N=38) 9 (23.7%) 29 (76.3%) LMCA (N=37) 16 (43.2%) 21 (56.8%) Basilar (n=22) 11 (50.0%) 11 (50.0%) Echocardiogram during Admission Wall Motion Abnormality (N=32) 9 (28.1%) 23 (71.9%) p=0.22 Elevated Serum Troponin during admission (>0.06 ng/ 14 (51.9%) 13 (48.1%) p<0.001** mL; N=27) EKG on Admission Arrhythmia (N=26) 8 (30.8%) 18 (69.2%) p=0.11* 16 (25.8%) 46 (74.2%) p=0.10

QTc Prolongation (>460ms; N=62) Table 3: Multivariate Logistic Regression Model for Prediction of Pulmonary Edema. Stroke location, with TIA serving as the reference category,

Age> historycontributed of diabetes significantly mellitus to (0.41,the multivariate 0.09-1.76), logistichistory regressionof heart failure model (5.22, predictive 0.94-28.96), of development history of hypertensionof the presence (1.78, or absence0.34-9.24), of pulmonaryhistory of smoking edema. (0.43,57 0.10-1.86), years (adjusted wall motion OR 1.40; abnormality 95% CI 0.25-7.68), noted on historyechocardiogram of atrial fibrillation during admission (1.81, 0.28-11.60), (0.50, 0.11-2.33), history troponinemia of coronary artery (3.42, disease 0.79-14.71), (0.93, presence 0.18-4.87), of this multivariate logistic regression model. arrhythmia on admission EKG (0.39, 0.05-2.77) and QTc prolongation (>460ms) on admission EKG (0.75, 0.18-3.17) did not contribute significantly to Adjusted Odds Ratio 95% Confidence Interval P Stroke Location RMCA 10.88 1.02-116.70 0.049 LMCA 76.44 6.93-843.54 <0.001 Basilar 29.23 1.90-449.51 0.02 without evidence of intercorrelations among the independent brainstem stroke (0.32) groups. The proportion of patients variables. Only having a RMCA stroke (adjusted OR 10.51, 95% CI with prolonged PR-intervals (>200ms; 2 (3, N=178) =7.62, 1.71-64.82) was predictive of having an elevated serum troponin p=0.06), arrhythmia ( 2 (3, N=201) =6.46, p=0.09), abnormal χ level. intraventricular conduction ( 2 (3, N=201) =2.58, p=0.46), or any ST-segment abnormalityχ ( 2 (3, N=201) =0.91, p=0.82) did not Electrocardiography vary across groups. χ χ Electrocardiograms were performed on 106 TIA control, The multivariate logistic regression model for presence of 37 RMCA, 36 LMCA and 22 brainstem stroke patients. The was different across groups ( 2 (3, N=201) =14.92, p=0.002), interval,a prolonged correctly QTc-interval classifying on admission 73.5% EKG of cases explained compared between to proportionwith the proportion of patients within with prolonged both the RMCA QTc-intervals (0.43) and (>460ms) LMCA 26.3% and 36.0% of the variance in having a prolonged QTc- χ (0.50) stroke groups being greater than for the TIA (0.20) and 2 (8) =8.09,p=0.43) without evidence of intercorrelations among baseline prediction rate of 63.7%, while fitting the data well (H-L χ J Neurol Transl Neurosci 2(1): 1040 (2014) 4/7 Probasco et al. (2014) Email: Central

Figure 1 Cardiopulmonary Response by Ischemic Stroke Location. A) Proportion of patients with pulmonary edema varied across stroke groups and was greatest

for patients with large vessel brainstem stroke. B) Myocardial dysfunction was defined as a composite outcome of wall motion abnormalities on echocardiogram, elevated groups, and was greatest among patients with large vessel left middle cerebral artery or right cerebral artery strokes involving the insula relative to control and large serum troponin, arrhythmia on admission EKG, and/or QTc-interval prolongation on admission EKG. Myocardial dysfunction also varied in proportion across stroke vessel brainstem stroke patients. * designates p<0.05 and *** designates p<0.001 by Fisher’s exact test. the independent variables. Only having a LMCA stroke (adjusted been suggested to play a primary role in precipitating raised hydrostatic pressure and elevated vascular permeability in the interval prolongation. pulmonary venous bed, similar to that seen in acute respiratory OR 4.55, 95% CI 10.77-19.24) was predictive of having QTc- Myocardial dysfunction which suggest that in ischemic stroke of the brainstem, pulmonary The proportion of patients with either wall motion edemadistress cansyndrome occur in(ARDS) the absence [11,18-21]. of cardiac Here we derangement present findings and abnormalities on echocardiogram, elevated serum troponin, stunned myocardium. The relationship of stroke location (i.e. whether of the on admission EKG varied across groups ( 2 (3, N=210) =16.87, anterior or posterior circulation, laterality) to the development p=0.001).arrhythmia Both on RMCA admission (0.68) EKG and and/orLMCA (0.60) prolonged stroke QTc-interval groups had of cardiac derangements and neurogenic pulmonary edema proportions greater than brainstem strokeχ (0.55) and TIA (0.35) following stroke is an open question. Cortical involvement in groups (Figure 1B). the development of cardiac derangements (e.g. dysrhythmia, Discussion been proposed to rely on connectivity of cortical regions, such In a limited retrospective case control study of patients asQTc the prolongation, medial prefrontal heart failure) cortex following and insular ischemic cortex, stroke with hasthe treated at a single tertiary medical center, large vessel ischemic hypothalamus, midbrain, pons and medulla [22]. The laterality stroke of the midbrain, pons, and/or medulla was associated with of infarction, whether right hemispheric or left, has been of the development of pulmonary edema independent of evidence of cardiac abnormalities typically associated with myocardial and sudden death [23-25]. Similarly, direct injury to the stunning. In contrast, both large vessel RMCA and LMCA strokes hypothalamus,unclear significance nucleus to the tractus development solitarius of and cardiac area derangementspostrema and with involvement of respective insular cortex were associated their respective sympathetic projections to the hypothalamus with pulmonary edema as well as cardiac abnormalities and spinal cord have been implicated in the generation of associated with myocardial stunning [5]. This suggests separate isolated neurogenic pulmonary edema [9]. In animal model brainstem pathophysiological mechanisms for pulmonary edema experiments, severe hypertension and neurogenic pulmonary with effects on the lungs but not the heart. edema have been induced by lesions to the hypothalamus as Neurogenic pulmonary edema and cardiac derangements, well as by irritation of the tractus solitarius nuclei of the medulla including stunned myocardium, have long been associated with while increased cardiac output, peripheral vascular resistance increased mortality in a variety of neurological diseases, from and hypertension have been induced by unilateral stimulation seizures and trauma to hemorrhagic and ischemic stroke [9,17]. of the area postrema of the medulla [9,26,27]. In animal models Catecholamine surge in the setting of injury to the diencephalon using phentolamine, an alpha-adrenergic antagonist active at the postganglionic adrenergic receptors, pulmonary edema has been prevented [26,27]. Hexamethonium, a preganlionic nicotinic and myocardium, brainstem is and thought neurogenic to cause pulmonary activation edema of independent both α- and acetylcholine receptors blocker caused reduction of serum ofβ-adrenergic myocardial receptors dysfunction within has both been the felt pulmonary to be a relatively venous rare bed catecholamine levels, reversal of hypertension, preservation of cardiac function, and prevention of hemorrhagic pulmonary phenomenon [9,10]. Specifically, sympathetic activation has J Neurol Transl Neurosci 2(1): 1040 (2014) 5/7 Probasco et al. (2014) Email: Central edema after pharmacological ablation of the nucleus tractus of interest and discloses support through grant RO1NS062059- solitarius [28]. 01A1 from the National Institute of Neurological Disorders and Stroke (National Institutes of Health, Rockville, Maryland). There are isolated case reports of treatment responsive neurogenic pulmonary edema treated with phentolamine References to interrupt cyclical hemodynamic instability and hypoxic 1. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, respiratory failure. This has been reported in the setting Flegal K, et al. Heart disease and stroke statistics--2009 update: a of progressively declining urine catecholamine levels [29]. report from the American Heart Association Statistics Committee and Fulminant neurogenic pulmonary edema has also been treated Stroke Statistics Subcommittee. Circulation. 2009; 119: 480-486. with prone positioning in ventilated patients [11]. 2. Dimant J, Grob D. Electrocardiographic changes and myocardial These experimental and clinical observations suggest damage in patients with acute cerebrovascular accidents. Stroke. cardiopulmonary compromise in the setting of central nervous 1977; 8: 448-455. system injury. This study suggests neurogenic pulmonary 3. Butcher KS, Parsons MW. Cardiac enzyme elevations after stroke: the edema in ischemic stroke can occur in the setting of large vessel infarction of the brainstem. This occurs independently 4. importanceAy H, Arsava of specificity.EM, SaribaÅŸ Stroke. O. Creatine2002; 33: kinase-MB 1944-1945. elevation after of concomitant cardiac involvement as indicated by elevated stroke is not cardiac in origin: comparison with troponin T levels. serum troponin levels, EKG changes, and altered wall motion on Stroke. 2002; 33: 286-289. echocardiography. This pattern of pulmonary edema independent 5. Kida K, Akashi YJ, Fazio G, Novo S. Takotsubo cardiomyopathy. Curr of cardiac involvement associated with large vessel brainstem Pharm Des. 2010; 16: 2910-2917. infarcts was markedly different from patterns observed in large vessel cortical strokes involving the RMCA and LMCA which were 6. Oppenheimer SM, Cechetto DF. Cardiac chronotropic organization of the rat insular cortex. Brain Res. 1990; 533: 66-72. also associated with objective signs of stunned myocardium. 7. White M, Wiechmann RJ, Roden RL, Hagan MB, Wollmering MM, This study is limited by its retrospective case-control design Port JD, et al. Cardiac beta-adrenergic neuroeffector systems in of data from a single tertiary facility with inherent potential acute myocardial dysfunction related to brain injury. Evidence for for selection and recall bias including incomplete clinical data catecholamine-mediated myocardial damage. Circulation. 1995; 92: available for review. This also includes the effect of lead-time bias 2183-2189. for the onset of pulmonary edema and variability in treatment 8. Oppenheimer S. Cerebrogenic cardiac arrhythmias: Cortical across cases [9,30] Ischemic stroke size may have varied between groups and was not controlled for in this study. The large 6-11.lateralization and clinical significance. Clinical autonomic research: official journal of the Clinical Autonomic Research Society. 2006; 16: small sample size of this study, warranting larger, prospective 9. Davison DL, Terek M, Chawla LS. Neurogenic pulmonary edema. Crit study.confidence Prospective intervals multi-center for multivariate studies analyses of the likely pulmonary reflect and the Care. 2012; 16: 212. cardiac derangements associated with ischemic stroke would 10. Burns JD, Green DM, Metivier K, DeFusco C. Intensive care management help to clarify the temporal relationship of infarction with of acute ischemic stroke. Emerg Med Clin North Am. 2012; 30: 713- cardiopulmonary derangements. 744. Conclusion 11. Marshall SA, Nyquist P. A change of position for neurogenic pulmonary edema. Neurocrit Care. 2009; 10: 213-217. In patients with large vessel brainstem infarction, unlike in patients with large vessel RMCA and LMCA strokes involving the 12. Tan CK, Lai CC. Neurogenic pulmonary edema. CMAJ: Canadian Medical Association journal = journal de l’Association medicale canadienne. insula, pulmonary edema can occur independent of myocardial 2007; 177: 249-250. stunning as analyzed by separate and composite cardiac endpoints including cardiac dysfunction, elevations of troponin 13. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, and abnormalities of electrical conduction. This suggests that statement for healthcare professionals from the American Heart neurogenic pulmonary edema can be caused by ischemia of Association/Americanet al. Definition and evaluation Stroke Associationof transient ischemicStroke Council; attack: Councila scientific on brainstem structures independent of cardiac dysfunction. Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the region of cerebrovascular involvement as well as brainstem the Interdisciplinary Council on Peripheral . The structuralConfirmation involvement of these findings and the in risk a prospective of neurogenic analysis and cardiogenic assessing pulmonary edema are required. as an educational tool for neurologists. Stroke. 2009; 40: 2276-2293. American Academy of Neurology affirms the value of this statement 14. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. Acknowledgement Guidelines for prevention of stroke in patients with ischemic stroke This work was supported through grant RO1NS062059-01A1 or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association from the National Institute of Neurological Disorders and Stroke, Council on Stroke: co-sponsored by the Council on Cardiovascular National Institutes of Health (NIH), Rockville, Maryland, USA. Radiology and Intervention: the American Academy of Neurology Conflicts of Interest 15. affirmsAberle DR,the value Wiener-Kronish of this guideline. JP, Webb Stroke. WR, 2006; Matthay 37: 577-617. MA. Hydrostatic versus increased permeability pulmonary edema: Diagnosis based on radiographic criteria in critically ill patients. Radiology. 1988; 168: 73-79. Dr. Probasco, Dr. Chang, and Dr. Victor have neither conflicts of interest nor disclosures to report. Dr. Nyquist reports no conflicts J Neurol Transl Neurosci 2(1): 1040 (2014) 6/7 Probasco et al. (2014) Email: Central

16. 24. Algra A, Gates PC, Fox AJ, Hachinski V, Barnett HJ; North American adjustment for antihypertensive medication. The Framingham Study. Symptomatic Carotid Endarterectomy Trial Group. Side of brain Stroke.D’Agostino 1994; RB, 25: Wolf 40-43. PA, Belanger AJ, Kannel WB. Stroke risk profile: infarction and long-term risk of sudden death in patients with symptomatic carotid disease. Stroke. 2003; 34: 2871-2875. 17. Nyquist P. Wet lungs and a battered brain stem: can we stop one if we cannot stop the other? Crit Care Med. 2013; 41: 1373-1374. 25. Laowattana S, Zeger SL, Lima JA, Goodman SN, Wittstein IS, Oppenheimer SM. Left insular stroke is associated with adverse 18. Hoff JT, Nishimura M, Garcia-Uria J, Miranda S. Experimental cardiac outcome. Neurology. 2006; 66: 477-483. neurogenic pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg. 1981; 54: 627-631. 26. Brown RH Jr, Beyerl BD, Iseke R, Lavyne MH. Medulla oblongata edema associated with neurogenic pulmonary edema. Case report. J 19. Neurosurg. 1986; 64: 494-500. the airways. I. Neurogenic stimulation induces plasma protein extravasationKowalski ML, into Did ier the A, rat Kaliner airway MA. lumen. Neurogenic Am Rev Respir Dis. 1989; in 27. Nathan MA, Reis DJ. Fulminating arterial hypertension with pulmonary 140: 101-109. edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat. Circ Res. 1975; 37: 226-235. 20. Minnear FL, Kite C, Hill LA, van der Zee H. Endothelial injury and pulmonary congestion characterize neurogenic pulmonary edema in 28. Lu WH, Hsieh KS, Lu PJ, Wu YS, Ho WY, Lai CC, et al. Hexamethonium rabbits. J Appl Physiol (1985). 1987; 63: 335-341. reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis. Crit 21. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in Care Med. 2013; 41: 1276-1285. human neurogenic pulmonary edema. Chest. 1997; 111: 1326-1333. 29. Davison DL, Chawla LS, Selassie L, Tevar R, Junker C, Seneff MG. 22. Verberne AJ, Owens NC. Cortical modulation of the cardiovascular Neurogenic pulmonary edema: successful treatment with IV system. Prog Neurobiol. 1998; 54: 149-168. phentolamine. Chest. 2012; 141: 793-795. 23. Colivicchi F, Bassi A, Santini M, Caltagirone C. Cardiac autonomic 30. Colice GL. Neurogenic pulmonary edema. Clin Chest Med. 1985; 6: derangement and arrhythmias in right-sided stroke with insular 473-489. involvement. Stroke. 2004; 35: 2094-2098.

Cite this article Probasco JC, Chang T, Victor D, Nyquist P (2014) Isolated Pulmonary Edema without Myocardial Stunning in Brainstem Strokes. J Neurol Transl Neurosci 2(1): 1040.

J Neurol Transl Neurosci 2(1): 1040 (2014) 7/7 Central Journal of Neurology & Translational Neuroscience Special Edition on Cerebrovascular Disease Elisabeth B. Marsh* and Rafael H. Llinas Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Edited by: Elisabeth B. Marsh Rafael H. Llinas Department of Neurology Department of Neurology The Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine Baltimore, MD, USA Baltimore, MD, USA

Prognostication/Recovery

The most elegant and useful solutions are simple. But oversimplification of a complicated topic is also problematic. Prognostication following cardiac arrest has become complex, requiring: a detailed cranial examination, EEG, SSEPs to evaluate the N20 response, and expensive laboratory testing (eg., neuron specific enolase). Over time, this has led to a more accurate, but less universally applicable assessment. Albaeni and colleagues propose a novel, three item score that is simple, fast, reproducible, and inexpensive, with a surprising degree of accuracy. Conversely, historically the prognosis and recovery of aphasia has been oversimplified into a single treatment algorithm, overlooking the subtleties that differentiate one syndrome from another. Tippett and colleagues highlight the heterogeneity of language disorders. The extent and precise location of pathway disruption may have significant repercussions on both choice of therapy and response Central Journal of Neurology & Translational Neuroscience

Research Article Special Issue on Predicting Survival with Good Cerebrovascular Disease Corresponding author Shaker M. Eid, Johns Hopkins School of Medicine, Neurological Outcome Within 24 Research Director, Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, 5200 Eastern Ave, MFL West 6th floor, Baltimore MD 21224, USA, Tel: 410-550- Hours Following Out of Hospital 5018. Fax: 410-550-2972. E-mail: Submitted: 12 January 2014 Cardiac Arrest:The Application Accepted: 20 January 2014 Published: 28 January 2014 and Validation of a Novel Copyright © 2014 Eid et al. Clinical Score OPEN ACCESS Aiham Albaeni1, Shaker M. Eid1*, Dhananjay Vaidya2 and Nisha Keywords • Cardiopulmonary resuscitation 3 Chandra-Strobos • Heart arrest 1Division of Hospital Medicine, Johns Hopkins University School of Medicine, Baltimore, • Sudden death Maryland, USA • Prognosis 2Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, • Survival Maryland, USA 3Division of Cardiology, Johns Hopkins Bayview Medical Center, USA

Abstract Background: Despite 50 years of research, prognostication post cardiac arrest traditionally occurs at 72 hours. We tested the accuracy of a novel bedside score within 24 hours of hospital admission, in predicting neurologically intact survival. Methods: We studied 192 adults following non-traumatic out-of-hospital cardiac arrest. In a 50% random modeling sample, a model for survival to discharge with good neurological outcome was developed using univariate analysis and stepwise multivariate logistic regression for predictor selection. The diagnostic efficiency of this modeled score was assessed in the remaining 50% sample using receiver operating characteristic (ROC) analysis. Results: In this study, 20% of patients survived to discharge with good neurological outcome. The final logistic regression model in the modeling sample retained three predictors: initial rhythm Ventricular Fibrillation, Return of Spontaneous Circulation ≤ 20 minutes from collapse, and Brainstem Reflex Score ≥ 3 within 24 hours. These variables were used to develop a three-point Out of Hospital Cardiac Arrest score. The area under the (ROC) curve was 0.84 [95% CI, 0.75-0.93] in the modeling sample and 0.92 [95% CI, 0.87-0.98] in the validation sample. A score ≥ 2 predicted good neurological outcome with a sensitivity of 79%, a specificity of 92%, and a negative predictive value of 93%. A score ≥1 had a sensitivity of 100% and a negative predictive value of 100%; however, the specificity was only 55%. Conclusion: This study demonstrates that a score based on clinical and easily accessible variables within 24 hours can predict neurologically intact survival following cardiac arrest.

Introduction identify those patients most likely to survive to hospital discharge so that precious medical resources can be appropriately allocated. Despite standardized care guidelines for cardiac arrest patients that are uniform in many countries, outcomes are varied Efforts have been devoted in the last 50 years to improve but remain generally poor [1,2]. Anoxic brain injury continues to be the major cause of death in this patient population. One of with one of the most important interventions being therapeutic the most important tasks for health care providers is to correctly survival following cardiopulmonary resuscitation (CPR) [2−4],

hypothermia [5,6]. Clinical trials have identified factors that are Cite this article: Albaeni A, Eid SM, Vaidya D, Chandra-Strobos N (2014) Predicting Survival with Good Neurological Outcome Within 24 Hours Following Out of Hospital Cardiac Arrest:The Application and Validation of a Novel Clinical Score. J Neurol Transl Neurosci 2(1): 1041. Eid et al. (2014) Email: Central associated with improved survival post arrest, and have put responders being AED equipped. The hospital serves a population forward predictive tools for such patients [7]. However, many of of more than one million, of which 71% are Caucasian. these predictive tools were developed in the 80s and 90s, prior Usual ICU Care to the advent of therapies like hypothermia that emerged in 2002 and require heavy sedation and the use of paralytics [5]. The decision to initiate therapeutic hypothermia was made No studies have commented on how such sedation affects CNS by an intensive care unit attending based on institutional recovery. Clinicians continue to rely on predictive tools that were guidelines. All patients treated with hypothermia received a developed in the 80s, while the relevance and applicability of standardized protocol of sedation with Fentanyl/Midazolam, reported on a complex predictive score of 11 items, for patients hours following which passive rewarming occurred. Paralytics withsuch in-hospitaldata to care cardiac in 2014 arrest is unclear. [8], the Althoughrelevance a of 2012 this predictivestudy has wereand paralytics then stopped (Vecuronium). and the use All of therapies sedation were was continued only for patient for 24 index to the broad more common entity of out of hospital arrest is comfort per Joint Commission on Accreditation of Healthcare unclear, due to the obvious heterogeneity of the two populations Organizations (JCAHO) guidelines [12]. For all other post arrest (i. e. inpatient Vs. outpatient cardiac arrest). patients (i. e. those not receiving hypothermia), sedation was based on clinical needs and was primarily for patient comfort We chose to develop and study a simple clinical tool that and was determined by the Richmond Agitation-Sedation Scale applies primarily to patients surviving out of hospital arrest, is not technology driven, and possesses the ease of clinical application in all hospitals regardless of resource availability. In addition, we (RAAS)Routine [13,14]. ICU care included a four hourly neurological sought a tool that would not only possess incremental accuracy assessment of the patient that involves assessment of Glasgow in predicting survival but also survival with good neurological outcome. RoutineComa Scale care (GCS), also pupillary included reflexes, stopping corneal all sedation reflexes, each gag/cough morning Methods toreflexes, perform oculocephalic accurate neurologic reflexes assessments and spontaneous and spontaneous breathing. Study design and population breathing trials (sedation holiday). Neurological assessments were usually performed by the nurses but also repeated Following Institutional Review Board (IRB) approval, we separately by the resident physicians, the ICU attending physician retrospectively studied 210 patients with non-traumatic out- and often the consulting neurologist. In case of discrepancy of-hospital cardiac arrest who survived to hospital admission between observers, the report of the attending/neurologist was patients were older than 18 years of age. Resuscitation was deliveredat a teaching by emergency university hospitalmedical servicebetween (EMS) 2004 personnel and 2010. and All selectedBrainstem to reflect Reflex the Score status (BRS)of the patient. the emergency department staff according to the American Heart Association (AHA) guidelines as temporally relevant [2,9]. Data were collected using Utstein guidelines [10,11]. Cardiac The brainstem reflex score (BRS) was clinically reported in 2006 and was derived from five brainstem reflexes (1-Pupillary givenreflex, equal 2-Corneal impact reflex, and assigned 3-Cough/Gag one point reflex, giving 4-Oculocephalic BRS a range arrest was defined as the absence of a palpable central pulse, act of attempting to maintain or restore life by establishing or fromreflex 0 (Doll’s(worst) eye), to 5 (best) 5-Spontaeous [15]. breathing). Each reflex was maintainingapnea, and unresponsiveness. airway, breathing Resuscitation and circulation was defined through as CPR, the Timing of neurological score assessment Sequential BRS scores were recorded for all patients during asdefibrillation a period of and 30 other seconds related or more emergency of restored care spontaneous techniques [10,11]. Return of spontaneous circulation (ROSC) was defined circulation [10,11]. Down time (time from collapse to CPR), time was used in the study whether therapeutic hypothermia was from CPR to return of spontaneous circulation (ROSC), and time applied24 hours or and not. the For highest patients score undergoing for each patient, hypothermia while offtherapy, sedation, the from collapse to ROSC were collected from EMS and emergency staff documentations. In case of unwitnessed arrest, the time initiation of paralytics and hypothermia. optimal 24-hour BRS score was primarily the BRS score prior to the time of collapse. Neurological outcome at discharge was Study variables and model development assessedof first detection according for to cardiac Glasgow-Pittsburgh arrest was used Cerebral as a substitute Performance for The goal was to develop a score that predicts survival with Categories scale (CPC) : CPC 1 is conscious and normal; CPC 2 good neurologic outcome after out-of-hospital cardiac arrest, conscious with moderate cerebral disability; CPC 3 conscious using variables accepted to be associated with improved survival. and CPC 5 death [11]. Patients with CPC 1 or 2 were considered VF, bystander CPR and duration to ROSC were associated with with severe cerebral disability; CPC 4 coma or vegetative state; Many studies have confirmed that an initial rhythm of VT/ were considered to have a bad neurologic outcome. were tested in univariate analysis including: initial rhythm VT/ to have a good neurologic outcome while those with CPC 3, 4 or 5 improved outcomes [16−21]. Hence these and other variables Regional EMS Service than or equal to 20 minutes from collapse [16,19], the presence The study hospital is located in Maryland, and serves a mixed VF [1, 16−18], return of spontaneous circulation (ROSC) less

of bystander CPR [16,20,21], Brainstem Reflex Score (BRS) urban community where EMS has a 2-tiered response with first within 24 hours post arrest more or equal to 3 [15,22], the use J Neurol Transl Neurosci 2(1): 1041 (2014) 2/8 Eid et al. (2014) Email: Central of therapeutic hypothermia [5,6], down time less or equal to 5 and care with the use of more negative predictive values of the score at different thresholds than three doses of epinephrine during CPR [27], witnessed were assessed drawal.in the validation The sensitivity, sample. specificity; positive and minutesarrest [1], [23,24], location age of lessarrest than [28], 75 and years gender [25,26], [29]. Results Patient group allocation Patient demographics Of 210 eligible patients, 18 were excluded for missing data. The remaining 192 patients were randomly divided into two During the study period, 210 consecutive patients were samples: a modeling sample of 96 patients and a validation admitted to the ICU with OHCA and 192 were analyzed after sample of 96 patients. meeting inclusion criteria. The modeling and validation samples were comparable in terms of major comorbidities (Table 1). The Data analysis All variables used were categorical and continuous variables and 27% African American. Coronary artery disease was present mean age was 64 years (SD±15), 52% were male, 72% Caucasian, were dichotomized. We tabulated descriptive statistics for both the modeling and validation samples. in 41%Cardiac of patients arrest characteristics and congestive are heart shown failure in Table in 35%. 2. The initial In the modeling sample, we worked to generate a predictive score. Univariate analyses were performed on all eleven variables rhythm was Ventricular Fibrillation or Tachycardia in 42 patients of interest to explore association with survival to discharge with good neurological outcome (cerebral performance category of outcome;(22%) ; 46 ROSC patients occurred (24%) within survived 20 minutes to hospital from discharge, collapse inof 1 or 2) using Chi square test. Variables that had a statistically those 38/46 (83%) survived to discharge with good neurological survival in univariate analyses were then included through a 76 patients (39 %). Brainstem reflex score was ≥3 within 24 forwardsignificant stepwise association selection (p<0.05) in a multivariable with neurologically logistic regression intact hours from admission in 44 patients (23%), and therapeutic model. theirhypothermia initial arrest was rhythm. used in 88 patients (46 %). Out of these 88 patients, 24 patients had VF/VT and 64 had PEA/Asystole as Univariate and multivariate analyses Eleven variables were tested in univariate analysis to VariablesBeta-coefficients were given ofan multivariateequal weight logisticof one score regression point if were the used to inform the building of a simplified prediction score. generate the prediction equation. Five variables emerged as being predictive of survival with good neurologic outcome; operating95% confidence characteristic intervals curveof the (ROC)beta coefficients analysis in overlapped. the validation The diagnostic efficiency of the score was assessed using the receiver 4 of which were associated with improved likelihood of neurologically intact survival, (initial rhythm of VF/VT, ROSC≤20 analysissample [30]. was Hosmer-Lemeshow performed to evaluate goodness model of performance fit test was usedwith minutes from arrest, BRS≥3 within 24 hours of arrest, and down regardsto assess to the ACLS fitness guidelines of the changes, developed therapeutic model, and hypothermia, sensitivity time ≤ 5 minutes) while the use of 3 or more doses of epinephrine during CPR worsened outcome (Table 3). The five variables were Table 1: Patient Demographics for Development and Validation Samples. All Patients Development Sample Validation Sample Characteristics P Value N=192 N=96 N=96 Mean age, years (SD) 62 (17) 0.07

Male sex, n (%) 10864 (15) (52) 6066 (62.5) (14) 0.08 Caucasians, n (%) 139 (72) 72 (75) 4867 (50)(70) Tobacco use, n (%) 136 (71) 65 (68) 0.420.39 End stage renal disease, n (%) 16 (8.3) 8 (8.3) 718 (8.3) (74) 1.00 CVA/TIA, n (%) 33 (17) 22 (23) 0.03

Diabetes Mellitus, n (%) 70 (36) 36 (37) 11 (11.4) 0.76 Hypertension, n (%) 138 (72) 70 (73) 6834 (71)(35) Cancer, n (%) 21 (22) 13 (13.5) 0.740.13 Peripheral vascular disease, n (%) 34 (18) 16 (16.6) 8 (8.3) 0.08 Coronary artery disease, n (%) 24 (12.5) 36 (37) 0.37 Congestive heart failure, n (%) 7868 (41)(35) 42 (44) 35 (36) 0.76 Chronic obstructive pulmonary disease, n (%) 63 (33) 33 (34) 30 (31) Hyperlipidemia, n (%) 33 (34) 35 (36) 0.64 Liver Disease, n (%) 1384 (6.7)(44) 495 (5.2) (51) 8 (8.3) 0.040.38 CVA/TIA : Cerebrovascular Accident/ Transient Ischemic Attack

J Neurol Transl Neurosci 2(1): 1041 (2014) 3/8 Eid et al. (2014) Email: Central

Table 2: Cardiac Arrest Characteristics in the Development and Validation Samples. All Patients Development Sample Validation Sample Characteristics P Value N=192 N=96 N=96 Witnessed arrest, n (%) 139 (72) 65 (68) Bystander CPR, n (%) 60 (31) 28 (29) 32 (33) 0.53 74 (77) 0.14 Initial Rhythm VF/VT, n (%) 20 (21) 22 (23) 0.72 76 (39) 35 (36) 0.37 42 (22) 106 (55) 51 (53) 55 (57) 0.56 ROSC ≤ 20 minutes, n (%) 41 (42) Hypothermia therapy, n (%) 0.56 Use of ≥3 doses of epinephrine, n (%) 19 (20) 25 (26) 0.30 88 (46) 46 (48) 42 (44) Survival to Hospital discharge with good neurological 38 (20) 19 (20) 19 (20) 1.00 BRSoutcome at 24 (CPC=1, hours ≥ 2), 3, nn (%)(%) 44 (23) 56 (58) 0.19 Arrest Location, n (%) Down time ≤ 5 minutes, n (%) 103 (54) 47 (49) Private 126 (66) 63 (66) 63 (66) 0.22 Public 16 (8.3) 5 (5.2) Other 50 (26) 22 (23) 28 (29) 11 (11.4) ROSC: return of spontaneous circulation, BRS: brain reflex score, CPR: cardiopulmonary resuscitation, VF/VT: ventricular fibrillation / ventricular tachycardia, CPC: cerebral performance category, Private Location: home, nursing home, Public Location: street or highway, public building, or other public property, Other Location: emergency department, ambulance, or clinic.

Table 3: Results of Univariate Analysis in the Development Sample. Gender Survivors with Good P Male 60 10 (17) 0.32 Study Variables N Neurological Outcome (CPC 1 Value or 2), n (%) Female 36 9 (25) Witnessed arrest Arrest Location Private 63 Yes 65 16 (25) 0.08 0.08 No 31 3 (10) Public 11 92 (14)(18) Bystander CPR Other 22 8 (36) ROSC: return of spontaneous circulation, BRS: brain reflex score, CPR: cardiopulmonary Yes 28 5 (18) 0.76 resuscitation, VF/VT: ventricular fibrillation / ventricular tachycardia, CPC; cerebral No 68 performance category, Private location: home, nursing home, Public location: street or highway, public building, or other public property, Other location: emergency department, Initial rhythm VF/VT 14 (21) ambulance, or clinic. Yes 20 0.01 No 76 subsequently included through a forward stepwise selection in 8 (40) developing a multivariable logistic regression model. 11 (14) ROSCYes ≤ 20 minutes 16 (39) No 4155 3 (5) <0.001 Multivariate analysis identified three predictive variables (key variables) that retained statistically significant association epinephrine with survival with good neurologic outcome (P<0.05) (initial Use of ≥3 doses of 0.009 Yes 51 5 (10) rhythm VF/VT, ROSC≤20 minutes, BRS≥ 3 within 24 hours) No (TablePrediction 4). score and validation

Hypothermia therapy 45 14 (31) Yes 0.33 develop a score that would predict the probability of survival with goodRegression neurological coefficients outcome. of Each the 3 variable key variables was given were an used equal to No 50 8 (16) 46 11 (24) weight as previously mentioned to generate a prediction score from 0 to 3 with the presence or absence of any combinations BRSYes within 24 hours ≥ 3 19 0.001 of these 3 key variables (Table 5). Of the patients who had only one favorable predictor (OHCA score=1), only 12% survived with No 77 109 (47) (13) good neurological outcome. The presence of any two favorable Yes 0.01 Down time ≤ 5 minutes the presence of all three favorable predictors (OHCA score=3) in No 47 145 (10) (30) anypredictors patient (OHCA further score=2) increased increased the probability the probability to 86%. to 64%, and 49 AgeYes ≥ 75 years 30 3 (10) 0.10 No 66 16 (25) the The area area under under the the curve curve was for 0.92the modeling sample was 0.84 [95% confidence interval (0.75-0.93) ]. In the validation sample [95% confidence interval J Neurol Transl Neurosci 2(1): 1041 (2014) 4/8 Eid et al. (2014) Email: Central

Table 4: 95% Confidence 95% Confidence VariablesBeta Coefficient and Odds Ratio ofBeta Multivariable Coefficient Logistic Regression Model. Odds Ratio P Value Interval Interval Initial rhythm VF/VT 1.65 0.28-3.02 5.21 1.32-20.53 0.018 2 0.005

ROSC≤ 20 minutes 1.63 0.61-3.400.27-2.99 7.455.11 1.84-30.181.31-19.91 0.019 BRS≥ VF/VT: 3 ventricular within 24fibrillation hours / ventricular tachycardia, ROSC: return of spontaneous circulation, BRS: brainstem reflex score.

Table 5: OHCA Score at Different Thresholds (95% CI). Probability of OHCA Score Sensitivity Specificity PPV NPV Survival 0 0% 100% 0% -

1 12% 100% 39%22% (28-50)(10-34) 100% 2 79% (66-92) 92%55% (88-96)(48-62) 72% (65-79) 93% (89-97) 3 86%64% 99% (98-100) 83% (77-89) 83% (77-89) OHCA: out-of-hospital cardiac arrest, PPV: positive predictive value, NPV:32% negative (17-47) predictive value.

arrest brain injury is common and often the major contributor to death [33]. Our study demonstrates a survival to discharge of the(0.87-0.98) validation ]. The sample P value (Supplement for goodness Table of fit 6). was Sensitivity 0.26, suggesting analysis showedthat the developed that our model model was reflected not affected the outcome by heterogeneity experienced in of 83% had a good neurological outcome (CPC 1, 2). These survival therapeutic hypothermia, care withdrawal, or changes in ACLS rates24% followingare directionally admission similar post to arrest. those Ofreported those dischargedby McNally alive,et al. guidelines. who reported that of those discharged post arrest 72 % had a good neurological outcome [1]. OHCA score sensitivity and specificity Survival probability (with good neurological outcome), Predictors of neurological outcome Efforts at prognosticating neurological recovery in cardiac negative predictive values (NPV) at different score points for arrest patients can be traced to the 1960s when the EEG was thesensitivity, validation specificity, sample are positive shown predictive in Table 5. value An OHCA (PPV), score and

reportedfirst used to on predict the poor outcome outcome and was of patients found to who be a poor have marker absent [95%≥ 2 predicted CI, 88-96%], survival a positive with predictive good neurological value of outcome72% [95% with CI, of recovery [34]. Several investigators have commented and 65-79%],a sensitivity and ofa negative 79% [95% predictive CI, 66-92%], value ofa specificity93% [95% ofCI, 92% 89- invokedpupillary for light predicting reflexes [7,22,35,36]. neurological However, survival. no Although single sign the presencepredicted of a favorablemyoclonus outcome. on day 1 Motor has been reflexes shown have to bealso a beenpoor 97%]. Alternatively, OHCA score ≥1 predicted good neurological prognosticator of outcome, the false positive rate can be as high andoutcome a 100% with negative a sensitivity predictive of 100%, value. a specificity of 55% [95% CI, 48-62%], a positive predictive value of 39% [95% CI, 28-50%] Discussion to prognosticate outcome given the likelihood that if one is using thisas 8.8% criterion [36]. Thus,alone, clinicians one may areerroneously reticent to miss use athis survivor finding nearly alone This study shows that a clinically derived simple prediction 10% of the time [36]. This has been the major criticism of relying tool comprised of 3 readily available variables (initial rhythm predict neurologically intact survival in out of hospital cardiac on motorIn 1985 reflexes Levy for et al.prognostication. developed a clinical prediction tool to arrestVF/VT, patients. ROSC ≤20 minutes, and BRS ≥ 3 within 24 hours) can identify patients most likely to recover following cardiac arrest. Although many other tools and algorithms have been evaluated, For many acute or chronic disease entities where outcomes the Levy paper remains the clinical corner stone for guiding clinical decision making in such patients [7]. The Levy study scoring systems to help identify patients more likely to have a examined neurological recovery on admission, day one, day are varied, the field of medicine has developed and validated good outcome or identify those at high risk for complications (e. three, one and two weeks after arrest. It relied on the presence or the purpose has been to better treat patients and also to better this study showed that only two out of 57 patients in whom eye- g. atrial fibrillation, pancreatitis) [31,32]. In all such instances allocate precious health care resources. No score is absolute, but closedabsence coma of brainstem lasts for threereflexes days to regainedpredict survival. independent The data function. from serves to guide clinical decision making. The fundamental goal of resuscitation is to maintain vital full recovery after coma lasting three days [37]. Thus evaluating Another study by Bell and Hodgson in 1974 reported the rarity of organ perfusion with the quintessential goal being good neurological status at day three emerged as the recommended neurological recovery. Despite great efforts and advances in time for recovery assessment. Levy reported that if pupillary optimizing the management of cardiac arrest victims, post cardiac light reflexes were absent, no patient survived while those with J Neurol Transl Neurosci 2(1): 1041 (2014) 5/8 Eid et al. (2014) Email: Central on day one recovered. after cardiac arrest, and is easy to use and implement in a busy preserved pupillary light reflexes and spontaneous movements environmentsurvival with suchpromising as the intensiveaccuracy careas early unit. as the first 24 hours Multiple studies have evaluated the role of somatosensory evoked potentials in predicting outcome after cardiac arrest, Effect of sedation and found that bilateral absence of N20 component after median Obviously when a paralytic is used, motor responses cannot nerve stimulation, can reliably predict death due to its low false be followed. Sedation on the other hand, to levels that are positive rates. However, the usefulness of the presence of N20 commonly used for patient comfort, should not impact brain response appeared to be limited due to low sensitivity and low positive predictive value [36,38,39]. obesity, and hypothermia delay the clearance of commonly used Years later and after the advent of therapeutic hypothermia, stem reflexes deleteriously. hence, the However,duration of it effect has been may shownchange thatbut these observations were broadly revalidated; however, the issue the magnitude of the effect should not be affected if sedation is of how hypothermia and its attendant sedation affect brainstem sedatives [44,45]; Several sedatives and drugs used nowadays sequester in the reliability of the neurological exam, median nerve sensory- andappropriately may thereby titrated contribute to a RASS to score delayed of negative awakening 1 or calling 2 [13,14]. into reflexes was poorly addressed. In 2011, Bouwes et al. restudied question the “three day rule” as suggested by Levy et al. Also, in predicting outcome post hypothermia therapy. The study hypothermia has been shown to decrease the metabolism of evoked potentials (SEP), and neuron-specific enolase (NSE) Fentanyl and Midazolam, commonly used for sedation post arrest and thus likely to affect the timing of neurological awakening demonstrated that the absence of pupillary light reflex, corneal However;reflex at 72 Zandbergen hours or the bilateral et al. questioned absence of the cortical usefulness N20 responses of SSEP almost universally used in post arrest patients. Therefore, the asof a the diagnostic median nerveor predictive could reliably tool since predict it appeared poor outcome to be subject [40]. [44,45]. This becomes extremely relevant since such drugs are is unclear. addition, our score is based on easily accessible variables that do applicability of the Levy observations to clinical practice in 2014 to noise interference and inter observer variability [41]. In Since a component of our score is assessment of brainstem interpretation and performance and might not be available in all not depend on technology that requires significant training for therapeutic hypothermia and sedation by calculating the best institutions. reflexes, our study circumvents the limitations imposed by Neurological assessment scores: limitations and before initiation of paralytics and therapeutic hypothermia in shortfalls patientsBRS score receiving during the this “sedation intervention. holiday” in the first 24 hours and Using the parameters discussed above in addition to key Clinical relevance and implications demographics, others have developed scores to predict survival The goal of this study was to develop a score that was after cardiac arrest. A prospective study by Geocadin et al. incremental, simple, easy to use in daily clinical practice, and reported that survivors had a higher initial median Brainstem able to accurately estimate survival with good neurological outcome (CPC 1,2) post arrest. The score consisted of three easily aReflex poor Scoreprognosis (BRS= [7,22]. 4) than those who died (BRS=2.5) [15]. The absence of light or corneal reflexes has also been associated with of arrest, initial rhythm VF/VT) and was found to be incremental A well-calibrated score by Adrie et al. that predicted survival inaccessible its association variables with (ROSC≤20 neurologically minutes, intact BRS≥3 survival. within If the24 hoursscore with good neurological outcome was developed on prospectively collected data and was validated in multiple institutions. predict survival with good neurological outcome. Additionally However, it was developed before the era of hypothermia and was ≥2, the sensitivity and specificity were high enough to validated on populations after the introduction of hypothermia an extremely low likelihood of survival. No patient scored zero anda score survived <2 had to a high hospital negative discharge predictive with value good (93-100%) outcome in with the variables on admission to predict survival with good neurological validation sample, and only one did in the development sample. outcome.[42]. Another It was score developed by Okada only et on al. patients utilized who five were readily treated available with The incremental nature of our score suggests that if all 3 hypothermia; thus, its usefulness in other post arrest patients is continued intensive care, while factoring in other clinical registry data base, a large prospective registry of in-hospital variables,variables are would present be more during likely the to first be rewarded 24 hours with after a arrest, good cardiacunknown arrest, [43]. ChanUsing etthe al. Get-with-the- developed a Guidelines-Resuscitationcomplex score of eleven probability of neurologically intact survival. variables to predict survival with good neurological outcome after in-hospital cardiac arrest. Although the score was detailed, Study limitations well calibrated, and developed on a large sample, it would be Several limitations of this study should be considered. First, clinically unwieldy to use due to its inherent complexity. Such a was internally validated on a sample size that is robust for most [8]. this study reflects a single institution experience where the score score would be difficult to remember or implement in a busy ICU As a result, there was a need for a simple clinical score that is 38 had good neurological outcomes). The original Levy study validated in cardiac arrest patients with and without therapeutic resuscitation studies (210 patients with 46 survivors of whom hypothermia, is capable of predicting neurologically intact this score is not intended to recommend further treatment; comprised 210 patients and the Adrie study 340 patients. Second,

J Neurol Transl Neurosci 2(1): 1041 (2014) 6/8 Eid et al. (2014) Email: Central however, if validated in a large prospectively collected data it has 6. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et the potential to be a useful tool in the hands of physicians to help al. Treatment of comatose survivors of out-of-hospital cardiac arrest guide aggressiveness of care and optimize the appropriate use of resources. Furthermore, prospective validation of such a score 7. withLevy induced DE, Caronna hypothermia. JJ, Singer N Engl BH, LapinskiJ Med. 2002; RH, 346: Frydman 557-563. H, Plum F. may help families in making decisions that are consistent with Predicting outcome from hypoxic-ischemic coma. JAMA. 1985; 253: their values and goals of care. Third, withdrawal of care in patients with poor prognosis has the potential of introducing a bias to the 8. 1420-1426.Chan PS, Spertus JA, Krumholz HM, Berg RA, Li Y, Sasson C, et al. A outcome examined in this population; however, when the model validated prediction tool for initial survivors of in-hospital cardiac was tested in patients who did not have withdrawal of care, all

9. arrest.ECC Committee, Arch Intern Subcommittees Med. 2012; 172: and 947-953. Task Forces of the American predictors of neurologically intact survival. Also, when we further Heart Association. 2005 American Heart Association Guidelines for three variables forming the score continued to be significant Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005; 112: IV1-203. eventested in the this difference subpopulation, between all three those variables variables’ can beta still coefficient, be given the difference was not significant (P value = 0.94) indicating that 10. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: accuracyan equal ofweight the score. in building Fourth, the despite final thesimple importance score from of SSEPs 0 to in3. registries: a statement for healthcare professionals from a task force predictingThus such biassurvival, did not this have technique a significant was not effect used on in the this predictive study as ofupdate the International and simplification Liaison of Committee the Utstein on templates Resuscitation for resuscitation (American our score relies on readily available clinical variables that can be Heart Association, European Resuscitation Council, Australian measured at any institution without the need for sophisticated Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, technology. Finally, the impact of percutaneous coronary intervention (PCI) on survival after out-of-hospital cardiac arrest 3385-3397. however, it Resuscitation Councils of Southern Africa). Circulation. 2004; 110: did not become a popular therapeutic tool until 2012 which is a 11. Cummins RO, Chamberlain DA, Abramson NS, Allen M, Baskett PJ, wastime recentlyperiod beyond established the analysis in multiple of this studies study [46,47]; and hence was not Becker L, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. A statement factored into the analytical design. for health professionals from a task force of the American Heart Conclusion Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Physicians continue to struggle with correctly prognosticating

12. CirculationJoint Commission 1991; 84: on 960-975. Accreditation of Healthcare Organizations, continues to use 1985 data to guide such decisions despite many Revisions to Anesthesia Care Standards: Comprehensive Accreditation survival post cardiac arrest. The field of resuscitation medicine therapeutic advents that directly call into question the validity Manual for Hospitals Oakbrook Terrace, IL. Joint Commission on of these observations. Multiple scores in recent years were Accreditation of Healthcare Organizations Department of Publications, developed to address the issue of prognostication but all were 2001. complex scores that employed clinical, laboratory and procedural 13. Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, et al. Monitoring sedation status over time in ICU patients: reliability score that has the potential to guide treatment and better triage and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. resources.inputs. We Further have identified testing of an this easy score to usein different incremental databases clinical is 2003; 289: 2983-2991.

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Cite this article Albaeni A, Eid SM, Vaidya D, Chandra-Strobos N (2014) Predicting Survival with Good Neurological Outcome Within 24 Hours Following Out of Hospital Cardiac Arrest:The Application and Validation of a Novel Clinical Score. J Neurol Transl Neurosci 2(1): 1041.

J Neurol Transl Neurosci 2(1): 1041 (2014) 8/8 Central Journal of Neurology & Translational Neuroscience

Review Article Special Issue on Aphasia: Current Concepts in Cerebrovascular Disease Corresponding author Donna C. Tippett, Department of Otolaryngology-Head Theory and Practice and Neck Surgery, Johns Hopkins University School of Donna C. Tippett1,2,3*, John K. Niparko4 and Argye E. Hillis1,3,5 Medicine, 601 N. Caroline Street, Baltimore, MD 21287, Tel: 410-955-7895, Email: 1Department of Neurology, Johns Hopkins University School of Medicine, USA Submitted: 21 December 2013 2Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, School of Medicine, USA Accepted: 20 January 2014 3Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Published: 28 January 2014 Medicine, USA Copyright 4Department of Otolaryngology-Head and Neck Surgery, University of Southern California, USA © 2014 Tippett et al. 5Department of Cognitive Science, Johns Hopkins University, USA OPEN ACCESS Abstract Keywords Recent advances in neuroimaging contribute to new insights regarding brain- • Stroke behavior relationships and expand understanding of the functional neuroanatomy • Aphasia of language. Modern concepts of the functional neuroanatomy of language invoke • Neuroanatomy rich and complex models of language comprehension and expression, such as dual • Dorsal and ventral streams stream networks. Increasingly, aphasia is seen as a disruption of cognitive processes • Rehabilitation underlying language. Rehabilitation of aphasia incorporates evidence based and person-centered approaches. Novel techniques, such as methods of delivering cortical brain stimulation to modulate cortical excitability, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, are just beginning to be explored. In this review, we discuss the historical context of the foundations of neuroscientific approaches to language. We sample the emergent theoretical models of the neural substrates of language and cognitive processes underlying aphasia that contribute to more refined and nuanced concepts of language. Current concepts of aphasia rehabilitation are reviewed, including the promising role of cortical stimulation as an adjunct to behavioral therapy and changes in therapeutic approaches based on principles of neuroplasticity and evidence-based/person-centered practice to optimize functional outcomes.

Abbreviations CNS: central nervous system; rTMS: repetitive transcranial an individual level, reintegration into school, work, and family magnetic stimulation; tDCS: transcranial direct current life may be unattainable given human dependence on the spoken stimulation; ICF: I word. Social isolation is a devastating and all too common LPAA: consequence of aphasia [4]. nternational Classification of Functioning, Disability, and Health; WHO: World Health Organization; Norman Geschwind wrote that “every behavior has an LifeIntro Participationductio Approachn to Aphasia anatomy” [5]. Language is no exception. Though complex in its underpinnings, the study of the structural and physiological basis of aphasia has been a major focus of neurological investigation Communication through language is central to the human since the mid-nineteenth century. However, we are now experience. The essential role of linguistic interaction in daily witnessing a revolution in the understanding of language and its disorders. Recent advances in neuroimaging contribute to function drives interpersonal connections key to health- a combined understanding of the structural and functional related quality of life. Interest in the study of language, and its correlates of language. In fact, in the morphometry and the rehabilitation, is fueled by the considerable impact of aphasia dynamic functioning measured with neuroimaging have emerged on both public and personal health, and by societal costs. Recent highly refined models of the neurobiological organization of estimates are that there are more than 795,000 strokes per year language. Extensive research has focused on the functional in the US [1]—the major source of aphasia incidence. Between neuroanatomy of language, with current models modifying the 1997 and 2006, the number of individuals with aphasia grew neurological model of language and promoting a dorsal-ventral by approximately 100,000 per year [2]. Aphasia is present in stream framework [6-9]. Similarly, advances in the study of 21-38% of acute strokes and associates with higher mortality, treatment of aphasia have resulted in adaptation of evidence morbidity, and healthcare resources consumed [3]. Costs for based and person-centered approaches to rehabilitation [10] stroke-related healthcare exceeded $25 billion in 2007 [1]. On as well as methods of delivering cortical brain stimulation to Cite this article: Tippett DC, Niparko JK, Hillis AE (2014) Aphasia: Current Concepts in Theory and Practice. J Neurol Transl Neurosci 2(1): 1042. Tippett et al. (2014) Email: Central

modulate cortical excitability, such as repetitive transcranial is increasing understanding of the complexity of language tasks, magnetic stimulation (rTMS) and transcranial direct current including underlying cognitive processes and representations stimulation (tDCS) [11,12]. that are needed to accomplish even basic tasks such as naming [33,34]. Recognition that focal neurodegenerative disease In this review, we discuss the historical context of the can cause primary progressive aphasia allows investigation foundations of neuroscientific approaches to language. We of language deficits caused by cerebral atrophy of regions of sample the emergent theoretical models of the neural substrates the brain not typically damaged by stroke [35]. This approach of language and cognitive processes underlying aphasia that to characterizing aphasia by disruption of specific cognitive contribute to more refined and nuanced concepts of language. processes is important for developing theories of how language Current concepts of aphasia rehabilitation are reviewed, is represented and processed [19]. Brain/language relationships including the promising role of cortical stimulation as an adjunct are further elucidated by technologies which introduce to behavioral therapy and changes in therapeutic approaches temporary dysfunction or suppress overactive areas associated based on principles of neuroplasticity and evidence-based/ withContemporary CNS insult, such paradigms as inhibitory of rTMS neural [36]. substrates of person-centeredHistorical practiceBackgr to optimizeound functional outcomes. language

The study of aphasia and its associated lesions in the late A principal concept of the functional neuroanatomy of nineteenth century by Dax [13], Broca [14,15], and Wernicke language holds that the processing needed to interpret the [16,17] led to many insights about the neural organization complex and multidimensional information in language, and of the language functions. The most reliable finding was that its context, requires an intricate division of bio-encoding labor. individuals who had language impairments were later found to One compelling model characterizes a dual stream: a ventral have damage to the left hemisphere at autopsy. Damage to the stream for mapping sound onto meaning, and a dorsal stream more anterior parts of the brain, particularly the left posterior for mapping sound onto motoric productions and articulation inferior frontal cortex, was often found in those whose spoken [6-9]. The brain computes a transform between thought and an output was limited or poorly articulated [15]; damage to the more acoustic signal transmitted across parallel, ascending pathways posterior regions in the left temporal lobe was found in those of the auditory brain stem and cortex [37] and executes parallel whose spoken output was well articulated but meaningless [17]. processing to synthesize input via interconnected neural These early observations established that language functions networks [38]. Support for this complex neural circuitry is found are localized in the left cerebral hemisphere and provided the in studies of the neocortex which show that there are vertically groundwork for Geschwind’s [18] seminal work on aphasia oriented columns of neurons perpendicular to the cortex [39]. classification and associated lesion sites. These classic aphasia classifications, such as Broca’s, Wernicke’s, global, conduction, A dual stream model of vision processing is well established. anomic, and transcortical aphasias, are vascular syndromes Studies of the primate visual cortex show that cells within a consisting of frequently associated deficits that reflect damage or column respond similarly to an external stimulus [40]. In the dysfunction of regions of neural tissue supplied by a particular original account, vision processing is divided into two streams: artery [19]. The characteristics of the classic aphasias are a ventral stream projecting to inferior temporal areas to process reviewed in detail by Damasio [20], Goodglass [21], and Hillis object identity (the “what” pathway) and a dorsal stream [19]. These syndromes are clinically useful in predicting areas of projecting to parietal areas to process object locations relative to ischemia and patterns of recovery, and in selecting rehabilitation the observer and other objects in the environment (the “where” approaches [19,22,23]. pathway) [41]. Subsequently, the function of the dorsal stream is expanded to include integration of visual input and motor Early accounts employed thoughtful correlations of site-of- responses (the “how” stream) which facilitate reaching and lesion and manifested behavior. Thus, from the context of brain grasping in visual space [42]. pathology, localization of normal function can be extrapolated [24]. It is important to note that individual variability in the The dual stream model of afferent information processing shape of the brain as well as the patterns of sulci and gyri renders is similarly applied to auditory processing in which the ventral only approximate localization of function [25,26]. stream processes “what” and the dorsal stream processes “where” [43], changes in the auditory signal over time [44], and auditory- Beginning in the 1980’s, advances in neuroimaging, including motor integration in which a sequence of sounds are heard and PET, functional MRI, and magnetoencephalography, expanded then spoken, the latter much like that in the visual domain [4,45]. understanding of the functional neuroanatomy of language by specifying the anatomical and functional correlates of central The dual stream model is extended to explain cortical nervous system (CNS) stations that support overall language organization of language. In this neuroanatomical model, function. Safe, noninvasive imaging of the brain reveals that proposed by Hickok, speech processing is defined as any task areas in both hemispheres of the brain are activated specifically involving aurally presented speech; speech perception refers during language tasks, although the left hemisphere shows more to any sub-lexical task; and speech recognition refers to the activation in the majority of neurologically normal adults [27- transformation of acoustic signals into a representation which 30], and that more distant areas of the cortex, such as inferior and accesses mental lexicon [7]. Speech perception involves auditory- anterior temporal cortex [31] and the basal ganglia and thalamus responsive areas in the superior temporal gyrus bilaterally, left [32], are also activated during language tasks. In addition, there more so than right. The processing system then diverges into J Neurol Transl Neurosci 2(1): 1042 (2014) 2/7 Tippett et al. (2014) Email: Central

two streams: a ventral stream which maps sound onto meaning, processing associated with the ventral stream and time- and a dorsal stream which maps sound onto articulatory-based dependent processing associated with the dorsal stream. The representations to yield production. The ventral stream is thus dorsal stream analyzes sequences of segments in time or space a sound-meaning interface responsible for processing speech and integrates sensorimotor input to support production; the signals for comprehension. In the dorsal stream, acoustic ventral stream extracts meaning independently of the temporal speech signals are translated into articulatory representations, or special sequences of linguistic elements [51]. essential for speech development and production, involving In addition, a novel dual lexicon framework, which builds on auditory-motor integration. The dual streams are also thought the dual stream model, is suggested to explain how and where to be bi-directional; the ventral stream mediates the relationship words are stored in the brain. Two lexica are proposed to provide between sound and meaning for perception and production, and an interface between linguistic subunits. The ventral lexicon is the dorsal system can also map motor speech representations an interface between phonetic and semantic representations. onto auditory speech representations [6,7] This area is not a store of semantic knowledge, but instead More recently, roles for the ventral and dorsal streams in retains morphologically organized representations of words to forward prediction are proposed. The role of forward prediction link acoustic phonetic representations to semantic content. The in speech perception is obvious; perception is dramatically dorsal lexicon is an interface between phonetic and articulatory improved when one knows what to listen for as cued by representations and houses articulatory organized-word form awareness of speaker, time, place, circumstance, and myriad Cognitiverepresentations, processes a concept underlying not previously aphasia endorsed [52]. additional contextual factors. Forward prediction from the motor system (dorsal stream) on speech perception is less clear. For example, transcranial magnetic stimulation studies show that Increasingly, aphasia is seen as a disruption of cognitive damage to the motor system does not result in deficits in speech processes underlying language tasks, such as sentence perception as would be expected if motor prediction is critical. An comprehension and naming. Cognitive representations are alternative hypothesis is that ventral stream forward prediction distributed across regions of the brain and activation of these enhances speech recognition [46]. various areas is needed to evoke semantic representations. For The ventral stream projects ventro-laterally and involves example, the semantic representation of a horse includes features cortex in the superior temporal sulcus and the posterior inferior of how it moves (middle temporal visual area and middle superior temporal lobe. The dorsal stream projects dorso-posteriorly temporal area), what it eats, and how it is used by humans [19]. toward the parietal lobe and ultimately to frontal regions [6,7,45]. Damage to specific areas of the brain may account for specific In contrast to prior models, speech processing is bilaterally patterns of impairments, such as selective naming deficits. organized, thus the ventral stream incorporates parallel Examples include the inability of an individual with visual processing, explaining why there are not substantial speech agnosia to name an item on visual confrontation, but demonstrate recognition deficits following unilateral temporal lobe damage preserved naming in response to a verbal description, and the [7]. The dorsal stream is strongly left dominant, accounting for toinability semantics of an given individual tactile with cues. optic aphasia to activate a semantic speech production deficits that are seen with dorsal temporal and representation given a structural description despite full access frontal lesions [47]. In addition, functional neuroimaging studies support bilateral organization of speech recognition as well as Modality-independent lexical access is also proposed as a neural circuit for auditory-motor interaction. For example, a mechanism to explain anomia commonly seen in several neurophysiologic recordings of normal subjects listening to aphasia subtypes. Individuals with anomia have intact semantic speech stimuli uniformly show bilateral activation in the superior representations, but cannot access phonological and/or temporal gyrus [6]. Imaging studies show that the left superior orthographic representations. Responses on convergent and posterior temporal region, located within the planum temporale, divergent naming tasks can include both semantic and phonemic is activated during speaking, naming, and humming [7,47]. errorsTreatment despite intact error awareness. A spatio-temporal language processing model is proposed to resolve theoretical inconsistencies in the dual stream approach [48]. For example, as stated earlier, one interpretation of the Aphasia treatment is progressively more informed by roles of the dual streams is that the ventral stream maps sound advances in understanding of the neurobiology of recovery and to meaning and the dorsal stream maps sound to articulation. learning. For example, tDCS is designed to facilitate synaptic Alternatively, the dorsal stream is thought to process complex plasticity [53]. rTMS can modify cortical excitability, increasing syntax whereas the ventral stream is thought to process simple or decreasing activity in targeted areas of the cortex. Protocols syntax [49]. employing rTMS improve naming in individuals with nonfluent aphasia. The mechanism proposed to explain this treatment These divergent proposals are unified in a spatio-temporal effect is suppression of over-active right hemisphere homologues model based on the Extended Argument Dependency model [54,55]. The promise of these methods relies on a full which assumes a cascaded architecture of language processing understanding of the anatomy of the neural networks underlying [50]. In this model, parallel systems process linguistic information language and variables that influence potential timing and extent that is both dependent and independent of temporal aspects of of structure-function reorganization. linguistic data flow. Ventral and dorsal streams are asserted to be engaged in sentence comprehension, with time-independent The multi-dimensionality of cortical reorganization and J Neurol Transl Neurosci 2(1): 1042 (2014) 3/7 Tippett et al. (2014) Email: Central

modifiability can be observed in the neuroplasticity producing simple sentences as disruption of the dorsal stream would be clinical recovery observed in response to stimulation [56]. expected; and in those with Wernicke’s aphasia, therapy may be Plasticity studies reveal the functional importance of the “use it directed at processing speech for comprehension or meaning in or lose it” principle and indicate that beneficial behavioral and sentences as disruption of the ventral stream would be expected. neural changes can be effected through intense and repetitive Further investigation is warranted regarding how the segregation practice [57]. Importantly, findings of recent investigations of of language functions described by this model suggests particular aphasia therapy emphasize that intense treatment for short approaches that promote “use” most effectively. One suggestion periods is more effective than a similar number of therapy is that ventral stream could be accessed by instructing patients to sessions over longer periods [58]. The rationale for early process the meaning of a target word during a repetition task in intervention in aphasia is also based on these neuroplasticity the treatment of conduction aphasia [68]. principles such that therapy capitalizes on spontaneous recovery Given the limitations of medical/clinician–centered models in the immediate post stroke period [59]. of therapy, a social model of therapy has emerged which While prosthetic stimulation offers a potentially important encompasses the authentic involvement of users (patients), adjunctive approach, behavioral therapy remains the mainstay creation of engaging experiences, user control, and accountability for treatment of aphasia. Behavioral therapy is both restitutivevidence- [10]. Person-centered practice “involves valuing the individual basedand compensatory. practice Current practice standards dictate that needs and rights of patients, understanding patients’ illness and therapy must be evidence-based and person-centered. E health care experiences, and embracing them within effective refers to an approach in which current, high- relationships which enable patients to participate in clinical quality research evidence is integrated with practitioner reasoning” [69, p. 68]. This practice is consistent with the expertise and client preferences and values [60]. The hierarchy conceptual framework for contemporary models of health care and generalizability of evidence are evaluated [61,62] and an of the International Classification of Functioning, Disability, and individual’s life circumstances, preferences, coping mechanisms, Health (ICF) of the World Health Organization (WHO) [70]. and concomitant medical, sensory, behavioral, and psychological issues are considered when making treatment decisions. The ICF is structured around the broad components of Because supportive, evidenced-based client-specific research body structures and functions, activities (related to tasks and can be difficult to identify, clinicians are advised to combine actions by individuals) and participation (involvement in life multiple, available studies of sufficiently good design, expert situations), and additional information regarding personal consensus, and clinical knowledge of anatomy and physiology and environmental factors. Language, cognition, voice, and to make reasonable judgments about the appropriateness and swallowing are body functions, and interpersonal interactions effectiveness of a specific treatment technique [63]. reflect the activity/participation component of the ICF, relevant to speech-language pathology. Family support and availability of Principles of neuroplasticity support early and intense communication partners are examples of environmental factors; therapy, however, questions remain regarding specific premorbid personalities, such as reticence versus extroversion, intervention strategies given the variable nature of aphasia. are factors germane to cognitive/communicative intervention. Historically, clinicians base therapy largely on assessment data. This framework encourages patient-centered care, focusing Therapy tasks are developed to target specific domains, such as on development of goals which address individual needs and auditory comprehension at sentence level or word retrieval at a circumstances. Therapy is a collaborative process. Patients, single word level. This approach follows a medical model which families, and caregiver identify goals which are important to emphasizes impairment of function, and is therapist-, rather than them. Clinicians conduct formal assessment, and then negotiation patient/person-, centered [64]. This circumscribed approach occurs between patients and therapists to define a treatment suffers from multiple limitations. Clearly, increased ability to plan. This is in contrast to therapist-controlled approaches; name pictured objects in a treatment task does not necessarily a genuine patient-centered approach allows patients, their translate to a relevant outcome, such as improvement in families, and caregivers to lead the goal setting process rather functional communication [65,66]. In addition, in their consumer than the clinician [64]. perspective, Dyke and Dyke [67] cite specific examples of the ways that impersonal approaches diminished the effectiveness of A critical approach to monitoring treatment effect requires rehabilitation therapies, and how linking therapy “to the person that clinicians document goals and outcomes for any relevant that (General Dyke) was and is, rather than to a generic set of component (e. g. , body structure/function, activity, participation). tools and techniques” (p. 150) maximizes outcome. Outcomes of treatment can then be measured for the specific modality that was treated, and/or at the activity/participation Application of principles governing brain organization level consistent with the ICF framework. For example, an activity and reorganization may contribute to the development of level goal may be “demonstrating the ability to speak in sentences” more meaningful therapy goals. For example, practice on a and the participation level outcomes are “engaging in a parent- confrontation naming task may facilitate the ability to convey teacher conference” and “giving a professional oral presentation” communicative intentions to listeners as a result of the adaptive [71]. The Quality of Communication Life Scale, which examines property of the brain. Treatment goals may also be reframed the impact of communication disorders on various aspects of based on the dual stream model of language organization. For quality of life, including relationships with others, communication example, in those with Broca’s aphasia, therapy may be directed interactions, and participation in activities, captures components at translating sound to motor speech productions to produce of the ICF health outcomes [72]. J Neurol Transl Neurosci 2(1): 1042 (2014) 4/7 Tippett et al. (2014) Email: Central

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Cite this article Tippett DC, Niparko JK, Hillis AE (2014) Aphasia: Current Concepts in Theory and Practice. J Neurol Transl Neurosci 2(1): 1042.

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