1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5a7ca02-6713-46cc-9ef3-0bb3e174d846] => Array
        (
            [runtime-id] => e5a7ca02-6713-46cc-9ef3-0bb3e174d846
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [00ad2428-a1c5-4719-98d3-280dc668ce8b] => Array
                        (
                            [runtime-id] => 00ad2428-a1c5-4719-98d3-280dc668ce8b
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [3f37ae8b-85f0-4181-a78a-86dbeefa46db] => Array
        (
            [runtime-id] => 3f37ae8b-85f0-4181-a78a-86dbeefa46db
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [1c4a1981-e8b3-48de-8a0e-087a54e42814] => Array
                        (
                            [runtime-id] => 1c4a1981-e8b3-48de-8a0e-087a54e42814
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [a98cb3e3-7700-4573-8afe-eaf7f39d0313] => Array
        (
            [runtime-id] => a98cb3e3-7700-4573-8afe-eaf7f39d0313
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [ad6c8e0f-25bf-434a-82c5-1812c3ced5f8] => Array
                        (
                            [runtime-id] => ad6c8e0f-25bf-434a-82c5-1812c3ced5f8
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [9d35507f-5814-481d-86c9-41dcabd7a874] => Array
        (
            [runtime-id] => 9d35507f-5814-481d-86c9-41dcabd7a874
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [84e1c600-5768-499f-9041-106547e28f77] => Array
                        (
                            [runtime-id] => 84e1c600-5768-499f-9041-106547e28f77
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [9d35507f-5814-481d-86c9-41dcabd7a874] => Array
        (
            [runtime-id] => 9d35507f-5814-481d-86c9-41dcabd7a874
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [84e1c600-5768-499f-9041-106547e28f77] => Array
                        (
                            [runtime-id] => 84e1c600-5768-499f-9041-106547e28f77
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5a7ca02-6713-46cc-9ef3-0bb3e174d846] => Array
        (
            [runtime-id] => e5a7ca02-6713-46cc-9ef3-0bb3e174d846
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [00ad2428-a1c5-4719-98d3-280dc668ce8b] => Array
                        (
                            [runtime-id] => 00ad2428-a1c5-4719-98d3-280dc668ce8b
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5a7ca02-6713-46cc-9ef3-0bb3e174d846] => Array
        (
            [runtime-id] => e5a7ca02-6713-46cc-9ef3-0bb3e174d846
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [00ad2428-a1c5-4719-98d3-280dc668ce8b] => Array
                        (
                            [runtime-id] => 00ad2428-a1c5-4719-98d3-280dc668ce8b
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5a7ca02-6713-46cc-9ef3-0bb3e174d846] => Array
        (
            [runtime-id] => e5a7ca02-6713-46cc-9ef3-0bb3e174d846
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [00ad2428-a1c5-4719-98d3-280dc668ce8b] => Array
                        (
                            [runtime-id] => 00ad2428-a1c5-4719-98d3-280dc668ce8b
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5a7ca02-6713-46cc-9ef3-0bb3e174d846] => Array
        (
            [runtime-id] => e5a7ca02-6713-46cc-9ef3-0bb3e174d846
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => Controlled
            [privilege] => Array
                (
                    [00ad2428-a1c5-4719-98d3-280dc668ce8b] => Array
                        (
                            [runtime-id] => 00ad2428-a1c5-4719-98d3-280dc668ce8b
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)
1naresh2naresh
Array
(
    [urn:ac.highwire.org:guest:identity] => Array
        (
            [runtime-id] => urn:ac.highwire.org:guest:identity
            [type] => guest
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [urn:ac.highwire.org:guest:privilege] => Array
                        (
                            [runtime-id] => urn:ac.highwire.org:guest:privilege
                            [type] => privilege-set
                            [privilege-set] => GUEST
                        )

                )

            [credentials] => Array
                (
                    [method] => guest
                )

        )

    [e5cdc199-5107-4e8c-838c-5c49e3e9ff98] => Array
        (
            [runtime-id] => e5cdc199-5107-4e8c-838c-5c49e3e9ff98
            [type] => toll-free-key
            [service-id] => ajnr-ac.highwire.org
            [access-type] => FreeToRead
            [privilege] => Array
                (
                    [fa429739-d4e1-45c1-a215-e41b64664afb] => Array
                        (
                            [runtime-id] => fa429739-d4e1-45c1-a215-e41b64664afb
                            [type] => toll-free-key
                        )

                )

            [credentials] => Array
                (
                    [method] => toll-free-key
                    [value] => tf_ipsecsha;658866c1c3f6af827369ef14fc22fbc44663175c
                )

        )

)


  
    






















































































































































    Symptom Differences and Pretreatment Asymptomatic Interval Affect Outcomes of Stenting for Intracranial Atherosclerotic Disease | American Journal of Neuroradiology  
    



















    

































    
  
  




    
    

  

      


    

      

  
  
  

    

  

    

  

                
    

      

  

    

  
      
  
  

    


Advertisement



  



  


  
  



  



    

  


  


  


  
  
  
  
  
  

  	      


    
      

    
  
    
        
    

  

    
                        

  

                
    

      

	  

		
		

			

			  

  
      
  
  

    

  
  
      
Research ArticleInterventional

  
      

  
      
Symptom Differences and Pretreatment Asymptomatic Interval Affect Outcomes of Stenting for Intracranial Atherosclerotic Disease
  
    	
M.D. Alexander, P.M. Meyers, J.D. English, T.R. Stradford, S. Sung, W.S Smith, V.V. Halbach, R.T. Higashida, C.F. Dowd, D.L. Cooke and S.W. Hetts

  
    	
American Journal of Neuroradiology June 2014,  35 (6) 1157-1162; DOI: https://doi.org/10.3174/ajnr.A3836 

  
  
  



  


  
  



			

		

	
	
 	
	  
  

		
		

			

			  

  
      
  
  

    
  


  
  



  
      
  
  

    

  

    

  
      
  
  

    
Abstract




BACKGROUND AND PURPOSE: Different types of symptomatic intracranial stenosis may respond differently to interventional therapy. We investigated symptomatic and pathophysiologic factors that may influence clinical outcomes of patients with intracranial atherosclerotic disease who were treated with stents.






MATERIALS AND METHODS: A retrospective analysis was performed of patients treated with stents for intracranial atherosclerosis at 4 centers. Patient demographics and comorbidities, lesion features, treatment features, and preprocedural and postprocedural functional status were noted. χ2 univariate and multivariate logistic regression analysis was performed to assess technical results and clinical outcomes.






RESULTS: One hundred forty-two lesions in 131 patients were analyzed. Lesions causing hypoperfusion ischemic symptoms were associated with fewer strokes by last contact [χ2 (1, n = 63) = 5.41, P = .019]. Nonhypoperfusion lesions causing symptoms during the 14 days before treatment had more strokes by last contact [χ2 (1, n = 136), 4.21, P = .047]. Patients treated with stents designed for intracranial deployment were more likely to have had a stroke by last contact (OR, 4.63; P = .032), and patients treated with percutaneous balloon angioplasty in addition to deployment of a self-expanding stent were less likely to be stroke free at point of last contact (OR, 0.60; P = .034).






CONCLUSIONS: More favorable outcomes may occur after stent placement for lesions causing hypoperfusion symptoms and when delaying stent placement 7–14 days after most recent symptoms for lesions suspected to cause embolic disease or perforator ischemia. Angioplasty performed in addition to self-expanding stent deployment may lead to worse outcomes, as may use of self-expanding stents rather than balloon-mounted stents.




ABBREVIATIONS:


BMS
balloon-mounted stent
ICAD
intracranial atherosclerotic disease
PTA
percutaneous transluminal angioplasty
SES
self-expanding stent


Intracranial atherosclerotic disease (ICAD) causes considerable morbidity and mortality, accounting for up to one-third of ischemic strokes in some series, particularly in certain populations.1⇓–3 Some lesions prove recalcitrant to first-line medical management, and, in recent decades, endovascular treatments have emerged and evolved as complementary therapies.4,5 Early series demonstrated technical feasibility and acceptable safety for percutaneous transluminal angioplasty (PTA) and then stent placement of lesions in ICAD.5⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓–17 Initially, intracranial procedures were performed with devices designed and approved for coronary interventions, with subsequent release of angioplasty balloons specifically engineered for intracranial use.5,12,17⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓–33 In 2005, the Wingspan stent system with Gateway PTA balloon catheter (Stryker, Kalamazoo, Michigan) became the first stent approved for treatment of ICAD in the United States.5,12,18⇓⇓⇓–22,25,34 Numerous studies reported progressively improved outcomes and low complication rates, but randomized data proving efficacy were lacking.5,12,18,20,24,25,35,36 In 2011, enrollment in the first randomized, controlled trial to evaluate stent placement versus medical management of ICAD, the Stent placement and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, was halted early due to high complication rates in the stent placement group as compared with the medical management group.4
The results of SAMMPRIS have elicited strong responses from both proponents and detractors of stent placement, with clinical decisions now changing.5 This current study retrospectively analyzes results of stent placement procedures performed for ICAD at 4 centers, with attention given to factors not specifically assessed in SAMMPRIS that may help guide further investigations of endovascular ICAD management.
MATERIALS AND METHODS


Under institutional review board–approved protocols, medical records were retrospectively examined by querying prospectively maintained procedure data bases at 2 large academic medical centers and 2 affiliated community hospitals, all of which have high-volume neurointerventional services. All patients who received stents for ICAD were evaluated. Patients with ICAD in whom stent placement was attempted but unsuccessful were included, as were patients with ICAD in whom PTA alone was planned but who received a stent to treat complications from PTA. Stent placement procedures performed during treatment of acute stroke were not included.


Information was gathered according to the guidelines of the Standards Committee of the Society for NeuroInterventional Surgery for investigations of endovascular treatment of ICAD.5 Presenting symptoms were noted and, as appropriate, further classified as “hypoperfusion” if clear evidence existed that reduced perfusion elicited ischemic symptoms. Examples of sufficient evidence of hypoperfusion etiology included reduced flow demonstrated on perfusion imaging, infarcts clearly located in a watershed distribution, and symptom exacerbation during known hypotension or on application of positional stressors. Symptoms that were probably caused by mixed subtypes were classified as indeterminate, as were symptoms that could not be clearly classified as hypoperfusion or nonhypoperfusion. Among nonhypoperfusion lesions, further classification divided them according to the duration of symptom-free interval before treatment. Ischemic symptoms were classified as TIA or stroke, the latter designated with permanent deficits or restricted diffusion on MR imaging. Specific medical comorbidities were considered present if a patient was treated for that condition; in the absence of treatment, the absence of a diagnosis was confirmed with clinical or laboratory data. Pretreatment antiplatelet or anticoagulation therapy other than procedural loading doses was noted. Functional status was evaluated by use of mRS, with a value assigned by authors performing data review on the basis of descriptions of functional performance in the medical record if a value was not formally noted.


The date of stent placement procedure and anesthesia type were recorded. Lesions were classified by vessel and furthest downstream vessel segment treated, listed in On-line Table 1. Lesion features and technical success were recorded according to those reported by the primary interventionalist, if available. When not explicitly stated, these data were assessed by investigators conducting data review. The degree of stenosis was determined by use of the Warfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID) technique.5,37 Stenosis length was measured, and Mori classification was assigned.38 The presence of tandem stenoses was noted, including stenoses in upstream extracranial vessel segments. Stent type, model, size, and number deployed were noted, as was performance of PTA during the same procedure. Postdeployment stenosis was measured in the same fashion as measurement before deployment. Technical success was defined as residual stenosis <50% without procedural complication.5 Any procedural complications were noted, as well as means taken to treat them, if applicable, and whether such complications were symptomatic. Complications occurring after procedure completion within 30 and 90 days of treatment were classified as peri-procedural and postprocedural, respectively.


The duration for postprocedure treatment with aspirin and clopidogrel was noted, as were use of glycoprotein IIb/IIIa inhibitors or any combination antiplatelet agents. Follow-up interval and duration were determined by the primary interventionalist, as was the technique of any follow-up imaging; no formal protocol existed between practitioners. The most recent date of contact was determined for long-term follow-up. For those patients with available records, the Social Security Death Index was queried to screen for deaths among patients lost to follow-up.39 In patients who died, death records were reviewed to evaluate cause of death.


End points evaluated were ischemic stroke, intraparenchymal hemorrhage, death, or other adverse event related to treatment at 30 days, 90 days, 1 year, 2 years, and point of last contact. Functional status was also assessed at these time points with the use of mRS. Data analysis was performed with the use of χ2 tests and logistic regression analysis by use of IBM SPSS version 20 (IBM, Armonk, New York).


RESULTS


Between June 1998 and December 2011, 142 lesions in 131 patients met inclusion criteria and had sufficient medical records for review. All sites in this study participated in the SAMMPRIS trial, but the few enrolled patients did not have data sufficient for inclusion in this study. Patient demographics, symptom features, and lesion characteristics are summarized in On-line Table 1. Technical success was achieved in 124 (87.3%) procedures. Treatment details and angiographic results are summarized in Table 1. Procedural complications occurred during treatment of 13 (9.2%) lesions, with 2 complications occurring during 1 procedure for the same lesion. Of these complications, two (1.4%) caused neurologic symptomatic sequelae. No permanent non-neurologic morbidity occurred from procedural complications. Mean follow-up time was 949 days (standard deviation, 1187; median, 413). Follow-up time exceeded 90 days for 101 (71.1%) lesions and 1 year for 79 (55.6%) lesions. Eighteen complications occurred in the postprocedural period, of which 13 were symptomatic. Thus, overall postprocedural complications occurred in 34 (23.9%) cases, with complications causing permanent symptomatic sequelae in 16 (11.3%) cases, summarized in On-line Table 2.


View this table:
Table 1: 
Treatment characteristics


No difference was noted in outcomes when comparing symptom types. Head-to-head comparison of hypoperfusion and nonhypoperfusion lesions showed correlation of the latter with new or recurrent stroke by last contact [χ2 (1, n = 63) = 5.41, P = .019]. Nonhypoperfusion lesions causing symptoms within 7 days of treatment were associated with stroke by last contact [χ2 (1, n = 136), 4.21, P = .047]. When considering nonhypoperfusion lesions causing symptoms within 14 days, the association was stronger [χ2 (1, n = 136) = 4.93, P = .032]. A trend was also noted for nonhypoperfusion lesions being correlated with complications occurring in the first 90 days after treatment, though this did not reach statistical significance [χ2 (1, n = 68) = 3.68, P = .051].


The results of univariate analysis are summarized in On-line Tables 3–9. Adverse events were more likely to occur in women and patients with diabetes, history of stroke, history of tobacco use, no diagnosis of hyperlipidemia, or no preprocedural antiplatelet therapy. Lesion features associated with death, stroke, or mRS >2 included basilar artery location, involvement of any basilar segment or petrous ICA, tandem lesions, Mori C classification, treatment with self-expanding stent (SES), and PTA performed in addition to SES deployment. Use of stents designed for intracranial use was associated with stroke, whereas stents designed for use elsewhere were associated with death.


In multivariate analysis (Table 2), patients treated with stents designed for intracranial deployment were less likely to be stroke free by last contact (OR, 0.060; 95% CI, 0.004–0.812; P = .034). This distinction did not predict rates of restenosis in this series. All 4 variables with statistically significant effects on mRS by last contact retained significance in the multivariate model. Absence of antiplatelet therapy and presence of tandem stenoses retained significance in prediction of death by last contact.


View this table:
Table 2: 
Multivariate models


DISCUSSION


ICAD causes a significant burden worldwide, accounting for 10–15% of strokes in series published from the United States and up to 33% in series from Asia.3,5,40 Many high-risk characteristics were demonstrated in the WASID trial, which also established the role for dual antiplatelet therapy in ICAD treatment, findings confirmed in this current study.37,40 Since the WASID trial, standard of practice in medical management has undergone a paradigm shift toward aggressive medical management that also includes lifestyle modifications, a shift that has now been accentuated by SAMMPRIS.5


Despite advances in medical therapy, some patients' symptoms recur. It is these patients for whom surgical and endovascular therapies were initially developed. Initial operative treatments showed promise, but subsequent examination in large trials showed no benefit of surgical intervention.41,42 Early endovascular treatment typically involved PTA alone, but residual stenosis >50% was common, and many patients had dissections that required stent placement.1,5,14,15,43 PTA also carries a risk for arterial perforation and is often counteracted acutely by vessel recoil.5 Thus, development of stent placement for ICAD was pursued.5


Initial reports demonstrated that intracranial stent placement can involve serious complications, dictating that such stents be used only in high-risk patients with medically refractory disease.9,10 However, with advances in stent placement technique and technology, both technical success rates and complication rates improved.5,24,25,44,45 On the basis of data from procedures with the use of devices designed for use in coronary arteries, technical success rates appeared to plateau around 95% with complications within the first 30 days after stent deployment occurring in approximately 7% of cases.5


The Wingspan system is the first device granted Food and Drug Administration approval for treatment of ICAD. Multiple series using this stent have been reported.12,18,24,25,35,36 The 2 largest nonrandomized, prospective series evaluating the device are the United States Wingspan registry, which reported a technical success rate of 98.8%, and the NIH Wingspan registry, which reported a rate of 96.7%.18,25 Restenosis >50% occurred in 27.9% and 25% of patients in these studies, respectively.18,25 In the current series, technical success occurred in 87.3% of cases, and restenosis >50% occurred in 13.4%.


The peri-procedural complication rates of the 2 registries (6.1% and 9.6%) approached that seen elsewhere for series that used other devices.18,25 Because of inconsistency in follow-up scheduling for this current retrospective study, 30-day outcomes were not consistently available. However, the comparable 90-day rate of any stroke and death was 14.8%. Excluding radiographic infarcts with no permanent symptomatic sequelae to most closely mirror outcomes measured in registries, the postprocedural complication was 11.3% in our series. By comparison, WASID did not report 90-day complications, but these end points occurred within 1 year in 15% of patients in the aspirin group.37


Given that nonrandomized series had suggested improving stent safety and efficacy, SAMMPRIS was disappointing when the trial was halted short of its planned enrollment size because of an unexpectedly high rate of stroke or death within 30 days of treatment in the stent placement (14.7%) versus medical arm (5.8%).4 No significant difference was noted between the groups beyond 30 days of enrollment, and the 1-year rate of stroke or death was 20.0% versus 12.2%, respectively.4 SAMMPRIS helped identify the path forward to identifying a role for safe, efficacious interventional treatment of ICAD, namely the reduction of peri-procedural complications through factors such as device improvement, peri-procedural blood pressure management, anesthetic techniques, and use of combination antiplatelet drugs. Additionally, appropriate patient selection criteria must be identified. Multiple factors must be considered in the design of the SAMMPRIS trial and its implications for future investigation.46


The SAMMPRIS trial made no distinction between pathophysiologic causes of symptoms. Our series shows that nonhypoperfusion lesions have higher risk of death at the point of last contact after stent placement. Additionally, multiple prior studies demonstrated that complication rates increase the sooner intervention is performed with relation to most recent symptoms, probably related to stability of atherosclerotic plaques.10,22,40,47 We posit that such concerns relate to unstable plaques that would be expected to cause primarily nonhypoperfusion symptoms, for example, embolization distal to the plaque or perforator occlusion adjacent to the plaque. In the current study, lesions causing nonhypoperfusion symptoms within 7 or 14 days of treatment were associated with stroke by point of last contact. Intervention timing, particularly for thromboembolic lesions, should be studied further. Optimum management also must be determined for lesions that do not afford sufficient asymptomatic windows. Additionally, stenosis caused by non-ICAD pathologies responds differently to endovascular treatment, shown by poor outcomes in patients without diagnosis of hyperlipidemia.


Before release of the Wingspan device, stent deployment to treat ICAD often required use of devices designed for coronary interventions.5 Treatment with a balloon-mounted stent (BMS) carries concern for dissection, vessel rupture, and recoil after deployment.1,43 With SES, wall stress persists longer than with BMS, causing more pronounced inflammation that causes neovascularization and neointimal hyperplasia.48 This may account for the higher rates of recurrent stenosis seen after treatment with SES compared with BMS, and it probably explains the lower rates of restenosis in this mixed SES/BMS study rather than the larger purely SES Wingspan studies.1,5,48⇓–50


The choice of intracranial stent has historically been driven by balancing potentially higher risks of BMS against greater residual stenosis and recurrence rates with SES. In this study, lesions treated with SES had worse rates of both stroke and death. Lesions treated with PTA in addition to SES had worse outcomes compared with treatment with BMS or SES without PTA. This could easily reflect bias, because more severe lesions may be more likely to be treated additionally with PTA. Severe lesions are also more likely to have poorer outcomes, as seen with Mori class C lesions in this series and elsewhere.1 This certainly bears further examination given that the technique used in SAMMPRIS required PTA before SES deployment. Interestingly, devices specifically designed for intracranial deployment had less favorable outcomes than other types. This may reflect reported operator difficulty with the Wingspan system.47,51,52 Future development of a BMS for intracranial use may affect results.


Limitations of this study result from its retrospective design. A lack of prospectively developed protocols for describing patient symptoms limited the analysis, particularly when attempting to discern treatment subtypes. Inadequate capture within early postprocedure periods limited direct comparison to other investigations. Although this study benefits from many years of data, it includes patients treated with methods formerly considered appropriate but not currently standard of care. Finally, all symptom and functional assessment was performed retrospectively by reviewing clinical follow-up documentation rather than formal standardized assessment, and follow-up was not standardized.


SAMMPRIS indicates that aggressive medical management should be the first-line treatment for ICAD. Further investigation must determine what treatments to offer for persistent symptoms and which patients are candidates for such treatment. Additionally, better metrics should be pursued that account for the nuances of symptoms from these lesions that can dramatically affect patients' lives but are not adequately captured by scales such as mRS.53 Randomized, controlled trials should be sought, and novel designs should be considered, such as group crossover or Bayesian enrollment, and any treatment performed outside such trials should be included in multicenter registries with standardized protocols to best evaluate outcomes.


CONCLUSIONS


ICAD causes significant morbidity and mortality. Treatment must begin with medical management, but certain patients will remain symptomatic despite aggressive measures. In such cases, a role for endovascular treatment remains undefined. The current study demonstrates that lesions causing symptoms as the result of reduced perfusion have more favorable outcomes after stent placement, and lesions causing nonhypoperfusion symptoms respond more favorably to stent placement when treated after a 7- to 14-day asymptomatic period. Currently available stents designed for intracranial use, SES deployment, and PTA in conjunction with SES deployment were associated with worse outcomes in the present study and warrant further examination.


Footnotes
  • Disclosures: Joey English: UNRELATED: Consultancy: Stryker Neurovascular, Silk Road Medical, Comments: Consultancy unrelated to intracranial stenting; Expert Testimony: Occasional medical legal work unrelated to intracranial stenting. Wade Smith—UNRELATED: Consultancy: Stryker*; Grants/Grants Pending: NIH; Royalties: University of California, Comments: Educational software; Stock/Stock Options: Multiple, Comments: I own mutual funds and some of these likely have investments in health care; I have stock in OrNim, Inc; Other: Ornim, Johnson and Johnson, Comments: The CEO of Ornim bought me coffee; I also serve on the DSMB for the VISSIT trial that studies the utility of an intracranial stent (J&J). Steven Hetts—UNRELATED: Grants/Grants Pending: Stryker Neurovascular,* Comments: Funding for the angiographic core laboratory at UCSF; Other: Stryker Neurovascular, Comments: In kind donation of statistical support services through Stryker Neurovascular Biostatistics division. In kind donation of organizational time by Kirsten Carrol of Stryker Neurovascular (*money paid to institution).
References
  1. 1.↵


    1. Jiang  WJ, 
    2. Cheng-Ching  E, 
    3. Abou-Chebl  A, 
    4. et al
    . Multicenter analysis of stenting in symptomatic intracranial atherosclerosis. Neurosurgery 2012;70:25–30
    CrossRefPubMed
  2. 2.↵


    1. Sacco  RL, 
    2. Kargman  DE, 
    3. Gu  Q, 
    4. et al
    . Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Stroke Study. Stroke 1995;26:14–20
    Abstract/FREE Full Text
  3. 3.↵


    1. Wong  LK
    . Global burden of intracranial atherosclerosis. Int J Stroke 2006;1:158–59
    CrossRefPubMed
  4. 4.↵


    1. Chimowitz  MI, 
    2. Lynn  MJ, 
    3. Derdeyn  CP, 
    4. et al
    . Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011;365:993–1003
    CrossRefPubMed
  5. 5.↵


    1. Hussain  MS, 
    2. Fraser  JF, 
    3. Abruzzo  T, 
    4. et al
    . Standard of practice: endovascular treatment of intracranial atherosclerosis. J Neurointerv Surg 2012;4:397–406
    Abstract/FREE Full Text
  6. 6.↵


    1. Lutsep  HL
    . Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004;35:1388–92
    Abstract/FREE Full Text
  7. 7.↵


    1. Miao  ZR, 
    2. Feng  L, 
    3. Li  S, 
    4. et al
    . Treatment of symptomatic middle cerebral artery stenosis with balloon-mounted stents: long-term follow-up at a single center. Neurosurgery 2009;64:79–84
    CrossRefPubMed
  8. 8.↵


    1. Mori  T, 
    2. Kazita  K, 
    3. Chokyu  K, 
    4. et al
    . Short-term arteriographic and clinical outcome after cerebral angioplasty and stenting for intracranial vertebrobasilar and carotid atherosclerotic occlusive disease. AJNR Am J Neuroradiol 2000;21:249–54
    Abstract/FREE Full Text
  9. 9.↵


    1. Levy  EI, 
    2. Horowitz  MB, 
    3. Koebbe  CJ, 
    4. et al
    . Transluminal stent-assisted angioplasty of the intracranial vertebrobasilar system for medically refractory, posterior circulation ischemia: early results. Neurosurgery 2001;48:1215–23
    CrossRefPubMed
  10. 10.↵


    1. Gupta  R, 
    2. Schumacher  HC, 
    3. Mangla  S, 
    4. et al
    . Urgent endovascular revascularization for symptomatic intracranial atherosclerotic stenosis. Neurology 2003;61:1729–35
    CrossRef
  11. 11.↵


    1. Jiang  WJ, 
    2. Wang  YJ, 
    3. Du  B, 
    4. et al
    . Stenting of symptomatic M1 stenosis of middle cerebral artery: an initial experience of 40 patients. Stroke 2004;35:1375–80
    Abstract/FREE Full Text
  12. 12.↵


    1. Bose  A, 
    2. Hartmann  M, 
    3. Henkes  H, 
    4. et al
    . A novel, self-expanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: the Wingspan study. Stroke 2007;38:1531–37
    Abstract/FREE Full Text
  13. 13.↵


    1. Gomez  CR, 
    2. Misra  VK, 
    3. Liu  MW, 
    4. et al
    . Elective stenting of symptomatic basilar artery stenosis. Stroke 2000;31:95–99
    Abstract/FREE Full Text
  14. 14.↵


    1. Marks  MP, 
    2. Marcellus  ML, 
    3. Do  HM, 
    4. et al
    . Intracranial angioplasty without stenting for symptomatic atherosclerotic stenosis: long-term follow-up. AJNR Am J Neuroradiol 2005;26:525–30
    Abstract/FREE Full Text
  15. 15.↵


    1. Marks  MP, 
    2. Wojak  JC, 
    3. Al-Ali  F, 
    4. et al
    . Angioplasty for symptomatic intracranial stenosis: clinical outcome. Stroke 2006;37:1016–20
    Abstract/FREE Full Text
  16. 16.↵


    1. Yu  W, 
    2. Smith  WS, 
    3. Singh  V, 
    4. et al
    . Long-term outcome of endovascular stenting for symptomatic basilar artery stenosis. Neurology 2005;64:1055–57
    CrossRef
  17. 17.↵


    1. Kim  DJ, 
    2. Lee  BH, 
    3. Kim  DI, 
    4. et al
    . Stent-assisted angioplasty of symptomatic intracranial vertebrobasilar artery stenosis: feasibility and follow-up results. AJNR Am J Neuroradiol 2005;26:1381–88
    Abstract/FREE Full Text
  18. 18.↵


    1. Fiorella  D, 
    2. Levy  EI, 
    3. Turk  AS, 
    4. et al
    . US multicenter experience with the Wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results. Stroke 2007;38:881–87
    Abstract/FREE Full Text
  19. 19.↵


    1. Fiorella  DJ, 
    2. Levy  EI, 
    3. Turk  AS, 
    4. et al
    . Target lesion revascularization after Wingspan: assessment of safety and durability. Stroke 2009;40:106–10
    Abstract/FREE Full Text
  20. 20.↵


    1. Henkes  H, 
    2. Miloslavski  E, 
    3. Lowens  S, 
    4. et al
    . Treatment of intracranial atherosclerotic stenoses with balloon dilatation and self-expanding stent deployment (WingSpan). Neuroradiology 2005;47:222–28
    CrossRefPubMed
  21. 21.↵


    1. Levy  EI, 
    2. Turk  AS, 
    3. Albuquerque  FC, 
    4. et al
    . Wingspan in-stent restenosis and thrombosis: incidence, clinical presentation, and management. Neurosurgery 2007;61:644–50
    CrossRefPubMed
  22. 22.↵


    1. Nahab  F, 
    2. Lynn  MJ, 
    3. Kasner  SE, 
    4. et al
    . Risk factors associated with major cerebrovascular complications after intracranial stenting. Neurology 2009;72:2014–19
    CrossRef
  23. 23.↵


    1. Turk  AS, 
    2. Levy  EI, 
    3. Albuquerque  FC, 
    4. et al
    . Influence of patient age and stenosis location on Wingspan in-stent restenosis. AJNR Am J Neuroradiol 2008;29:23–27
    Abstract/FREE Full Text
  24. 24.↵


    1. Yu  SCH, 
    2. Leung  TWH, 
    3. Lee  KT, 
    4. et al
    . Angioplasty and stenting of atherosclerotic middle cerebral arteries with Wingspan: evaluation of clinical outcome, restenosis, and procedure outcome. AJNR Am J Neuroradiol 2011;32:753–58
    Abstract/FREE Full Text
  25. 25.↵


    1. Zaidat  OO, 
    2. Klucznik  R, 
    3. Alexander  MJ, 
    4. et al
    . The NIH registry on use of the Wingspan stent for symptomatic 70–99% intracranial arterial stenosis. Neurology 2008;70:1518–24
    CrossRef
  26. 26.↵


    1. Kessler  IM, 
    2. Mounayer  C, 
    3. Piotin  M, 
    4. et al
    . The use of balloon-expandable stents in the management of intracranial arterial diseases: a 5-year single-center experience. AJNR Am J Neuroradiol 2005;26:2342–48
    Abstract/FREE Full Text
  27. 27.↵


    1. Hatano  T, 
    2. Tsukahara  T, 
    3. Ogino  E, 
    4. et al
    . Stenting for vertebrobasilar artery stenosis. Acta Neurochirurgica Suppl 2005;94:137–41
    CrossRef
  28. 28.↵


    1. Lee  TH, 
    2. Kim  DH, 
    3. Lee  BH, 
    4. et al
    . Preliminary results of endovascular stent-assisted angioplasty for symptomatic middle cerebral artery stenosis. AJNR Am J Neuroradiol 2005;26:166–74
    Abstract/FREE Full Text
  29. 29.↵


    1. Chow  MM, 
    2. Masaryk  TJ, 
    3. Woo  HH, 
    4. et al
    . Stent-assisted angioplasty of intracranial vertebrobasilar atherosclerosis: midterm analysis of clinical and radiologic predictors of neurological morbidity and mortality. AJNR Am J Neuroradiol 2005;26:869–74
    Abstract/FREE Full Text
  30. 30.↵


    1. Lylyk  P, 
    2. Vila  JF, 
    3. Miranda  C, 
    4. et al
    . Endovascular reconstruction by means of stent placement in symptomatic intracranial atherosclerotic stenosis. Neurol Res 2005;27(Suppl 1):S84–88
    CrossRefPubMed
  31. 31.↵


    1. Boulos  AS, 
    2. Agner  C, 
    3. Deshaies  EM
    . Preliminary evidence supporting the safety of drug-eluting stents in neurovascular disease. Neurol Res 2005;27(Suppl 1):S95–S102
    CrossRefPubMed
  32. 32.↵


    1. Abou-Chebl  A, 
    2. Bashir  Q, 
    3. Yadav  JS
    . Drug-eluting stents for the treatment of intracranial atherosclerosis: initial experience and midterm angiographic follow-up. Stroke 2005;36:e165–e168
    Abstract/FREE Full Text
  33. 33.↵


    1. Abou-Chebl  A, 
    2. Krieger  DW, 
    3. Bajzer  CT, 
    4. et al
    . Intracranial angioplasty and stenting in the awake patient. J Neuroimaging 2006;16:216–23
    CrossRefPubMed
  34. 34.↵


    1. Costalat  V, 
    2. Maldonado  IL, 
    3. Vendrell  JF, 
    4. et al
    . Endovascular treatment of symptomatic intracranial stenosis with the Wingspan stent system and Gateway PTA balloon: a multicenter series of 60 patients with acute and midterm results. J Neurosurg 2011;115:686–93
    CrossRefPubMed
  35. 35.↵


    1. Lanfranconi  S, 
    2. Bersano  A, 
    3. Branca  V, 
    4. et al
    . Stenting for the treatment of high-grade intracranial stenoses. J Neurol 2010;257:1899–908
    CrossRefPubMed
  36. 36.↵


    1. Zhao  ZW, 
    2. Deng  JP, 
    3. He  SM, 
    4. et al
    . Intracranial angioplasty with Gateway-Wingspan system for symptomatic atherosclerotic stenosis: preliminary results of 27 Chinese patients. Surg Neurol 2009;72:607–11
    CrossRefPubMed
  37. 37.↵


    1. Chimowitz  MI, 
    2. Lynn  MJ, 
    3. Howlett-Smith  H, 
    4. et al
    . Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305–16
    CrossRefPubMed
  38. 38.↵


    1. Mori  T, 
    2. Fukuoka  M, 
    3. Kazita  K, 
    4. et al
    . Follow-up study after intracranial percutaneous transluminal cerebral balloon angioplasty. AJNR Am J Neuroradiol 1998;19:1525–33
    Abstract
  39. 39.↵


    1. Quinn  J, 
    2. Kramer  N, 
    3. McDermott  D
    . Validation of the Social Security Death Index (SSDI): an important readily-available outcomes database for researchers. West J Emerg Med 2008;9:6–8
    PubMed
  40. 40.↵


    1. Kasner  SE, 
    2. Chimowitz  MI, 
    3. Lynn  MJ, 
    4. et al
    . Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113:555–63
    Abstract/FREE Full Text
  41. 41.↵


    1. Powers  WJ, 
    2. Clarke  WR, 
    3. Grubb  RL  Jr., 
    4. et al
    . Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the carotid occlusion surgery study randomized trial. JAMA 2011;306:1983–92
    CrossRefPubMed
  42. 42.↵


    1. Powers  WJ, 
    2. Grubb  RL  Jr., 
    3. Raichle  ME
    . Clinical results of extracranial-intracranial bypass surgery in patients with hemodynamic cerebrovascular disease. J Neurosurg 1989;70:61–67
    CrossRefPubMed
  43. 43.↵


    1. Nguyen  TN, 
    2. Zaidat  OO, 
    3. Gupta  R, 
    4. et al
    . Balloon angioplasty for intracranial atherosclerotic disease periprocedural risks and short-term outcomes in a multicenter study. Stroke 2011;42:107–11
    Abstract/FREE Full Text
  44. 44.↵


    1. Chamczuk  AJ, 
    2. Ogilvy  CS, 
    3. Snyder  KV, 
    4. et al
    . Elective stenting for intracranial stenosis under conscious sedation. Neurosurgery 2010;67:1189–93
    CrossRefPubMed
  45. 45.↵


    1. Samaniego  EA, 
    2. Hetzel  S, 
    3. Thirunarayanan  S, 
    4. et al
    . Outcome of symptomatic intracranial atherosclerotic disease. Stroke 2009;40:2983–87
    Abstract/FREE Full Text
  46. 46.↵


    1. Patel  RD, 
    2. Saver  JL
    . Evolution of reperfusion therapies for acute brain and acute myocardial ischemia: a systematic, comparative analysis. Stroke 2013;44:94–98
    Abstract/FREE Full Text
  47. 47.↵


    1. Tarr  RW, 
    2. Albuquerque  F, 
    3. Hirsh  J, 
    4. et al
    . The SAMMPRIS trial: the end or just the beginning. J Neurointerv Surg 2011;3:310–11
    FREE Full Text
  48. 48.↵


    1. Shofti  R, 
    2. Tio  F, 
    3. Beyar  R
    . Neointimal vascularization and intimal thickening in response to self-expanding stents: a swine model. Int J Cardiovasc Intervent 2004;6:61–67
    PubMed
  49. 49.↵


    1. Fiorella  D, 
    2. Chow  MM, 
    3. Anderson  M, 
    4. et al
    . A 7-year experience with balloon-mounted coronary stents for the treatment of symptomatic vertebrobasilar intracranial atheromatous disease. Neurosurgery 2007;61:236–42
    CrossRefPubMed
  50. 50.↵


    1. Groschel  K, 
    2. Schnaudigel  S, 
    3. Pilgram  SM, 
    4. et al
    . A systematic review on outcome after stenting for intracranial atherosclerosis. Stroke 2009;40:e340–347
    Abstract/FREE Full Text
  51. 51.↵


    1. Yu  SC, 
    2. Leung  TW, 
    3. Lee  KT, 
    4. et al
    . Learning curve of Wingspan stenting for intracranial atherosclerosis: single-center experience of 95 consecutive patients. J Neurointerv Surg 2014;6:212–18
    Abstract/FREE Full Text
  52. 52.↵


    1. Rahme  RJ, 
    2. Aoun  SG, 
    3. Batjer  HH, 
    4. et al
    . SAMMPRIS: end of intracranial stenting for atherosclerosis or back to the drawing board? Neurosurgery 2011;69:N16–N18
    PubMed
  53. 53.↵


    1. Rasmussen  PA
    . Stroke outcome measures: a tale of two trials. J Neurointerv Surg 2013;5:393–94
    FREE Full Text
  • Received May 21, 2013.
  • Accepted after revision October 17, 2013.
View Abstract
  


  
  



  
      
  
  

    
  


  
  



  




  


  
  



  
      
  
  

    
  


  
  



  
      
  
  

     Back to top  


  
  



			

		

		
		

			

			  

  
        
In this issue

    
  
  

    
  


  
  



  
      
  
  

    

  

    

  
      
  
  

    


Advertisement



  



  


  
  



  



  


  
  



  
      
  
  

    

	  
  

		

          

            

  
      
  
  

     Print  


  
  



  
      
  
  

     Download PDF  


  
  



  
      
  
  

    
 Email Article
  


  
  



  
      
  
  

    
 Citation Tools
  


  
  



          

        

        
        

          

            



  
      
  
  

    

  

    

  
      
  
  

    

  
  
  
  
      
Symptom Differences and Pretreatment Asymptomatic Interval Affect Outcomes of Stenting for Intracranial Atherosclerotic Disease
  
    	
M.D. Alexander, P.M. Meyers, J.D. English, T.R. Stradford, S. Sung, W.S Smith, V.V. Halbach, R.T. Higashida, C.F. Dowd, D.L. Cooke, S.W. Hetts

  
    	
American Journal of Neuroradiology Jun 2014, 35 (6) 1157-1162; DOI: 10.3174/ajnr.A3836 

  
  
  



  


  
  



  
      
  
  

    

  
    
  
  
    
  
  
    
  


  


  
  



  
      
  
  

    
del.icio.us logo Twitter logo Facebook logo Mendeley logo
  


  
  



  



  


  
  



  
      
  
  

    
  


  
  



          

        

	
 	
	
	


  


  
  



  
      
  
  

    
              Purchase  


  
  



  
        
Jump to section

    
  
  

    
  


  
  



  
      
  
  

    
  


  
  



			

		

	
	
 	
	
	


    

  



  

                
    

      

  

    

  
      
  
  

    


Advertisement