Current Advances in Rapid Stroke Diagnosis

1

At a rural acute stroke-ready hospital in the year 2030, you are using a tele-stroke tablet to evaluate a 62-year-old male en route by mobile computed tomography (CT) ambulance. The man’s wife says he complained of left-sided weakness for the past 2 hours. A computer downloads the 20 non-contrast head CT images transmitted from the ambulance, but some of them are blurry. “Again?” the radiology tech exclaims. “These budget cuts are killing us. In the city they have ambulances that give you 300 high-definition images, in half the time!” Via the tele-stroke tablet, you find that the patient has an NIH stroke scale score of 8. The patient’s vital signs, ECG, PT-INR, and glucose are within normal limits, and a “GFAP” is below the threshold for thrombolysis exclusion. You wonder if you missed a bleed in the blurry CT images. The ambulance is 10 minutes away, and the nearest primary stroke center is 1 hour away by air. The paramedic in the ambulance speaks. “We have tPA ready. Should we administer before arrival?”

Stroke is the fifth leading cause of death in the United States, accumulating health care costs of up to $33.6 billion each year.1,2 Eighty-seven percent of strokes are ischemic in etiology, and thrombolysis with intravenous tissue-type plasminogen activating factor (tPA) is the only FDA approved treatment for acute ischemic stroke.2 An estimated 1.9 million neurons are lost every minute that treatment is delayed, and the American Heart Association/American Stroke Association (AHA/ASA) recommends tPA administration within 3 to 4.5 hours of symptom onset and within 1 hour of hospital arrival.3-6 The gold standard for stroke diagnosis is head CT, and an initial non-contrast CT is essential to exclude hemorrhagic stroke or intracerebral hemorrhage, a major contraindication to tPA administration. Per AHA/ASA acute ischemic stroke treatment recommendations, providers have a 1-hour “door-to-needle” time between hospital arrival, CT imaging and review, and tPA administration.6

However, a national multicenter study from 2011 found that fewer than 30% of stroke patients had door-to-needle times of one hour or less.7 Furthermore, the Target:Stroke quality improvement initiative launched by ASA/AHA in 2010 found an improvement in this number to only 53.3%, even after their quality improvement interventions.8

Access also contributes to delayed tPA administration. Some studies found that less than 20 to 60% of stroke patients access a hospital within 3.5 hours of symptom onset, and in 2010, 55.4% of the United States population lived at least 1 hour away from hospitals with stroke treatment capabilities.9-11

There are a variety of ways to promote rapid recognition, diagnosis, and management of acute ischemic stroke. The Face Arm Speech Test (FAST), Cincinnati Prehospital Stroke Scale (CPSS), and Los Angeles Prehospital Stroke Scale (LAPSS) are assessment tools frequently used in the prehospital setting by emergency medical services personnel, with high predictive value for stroke based on patient signs and symptoms.12

Additionally, the Joint Commission accredits Primary Stroke Centers, or hospitals with adequate resources and protocols for stroke management as defined by AHA/ASA.13

Scientific and technological advances in the past 20 years have revealed the following new ways to improve early stroke recognition and management.

Tele-stroke Networks

Telemedicine has advanced significantly over the past decade, broadening regional access to quality stroke management. Cellular connectivity with fourth generation long-term evolution (4G LTE) broadband has expanded the ability of neurologists to assess stroke patients more reliably via mobile devices like tablets.14,15 Most recently, in a study of 259 consecutive stroke patients evaluated by tele-stroke providers, the mean door-to-needle time was 42.2 minutes.16 The Joint Commission claims that tele-stroke networks are the best option for stroke management in rural areas, and in 2015 created a new certification for “Acute Stroke-Ready Hospitals” with tele-stroke provider access and tPA administration capabilities, among other requirements.17-19

Mobile Stroke Treatment Units

In Germany and the United States, researchers have investigated the viability of mobile CT imaging to exclude hemorrhagic stroke in the pre-hospital setting, thereby expediting tPA treatment.

PHANTOM-S

In Berlin, the Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke Study (PHANTOM-S) used Stroke Emergency Mobile (STEMO) units. STEMO units are ambulances with a CT scanner, laboratory equipment for point of care testing, paramedics, a radiology technician, and a neurologist. For 200 ischemic stroke patients treated with tPA by STEMO, the mean alarm-to-treatment time was 25 minutes shorter than in the control group (51.8 vs. 76.3 minutes, respectively, P<.001). tPA was used more frequently with STEMO deployment (32.6% vs. 21.1%) yet the risk of developing intracerebral hemorrhage was lower, albeit statistically insignificant.20-21 Overall, they estimated an annual reduction of 18 disabilities and a gain of 29 quality-adjusted life years for acute ischemic stroke patients who were treated with STEMO.

PHAST

The Cleveland Pre-Hospital Acute Stroke Treatment (PHAST) study used Mobile Stroke Treatment Units (MSTUs). MSTUs are similar to STEMO units, but a vascular neurologist evaluates the patient via telemedicine, and a neuro-radiologist reviews CT images remotely. The mean time for patients entering MSTUs to completing the head CT was 5 minutes faster than patients who received conventional stroke care (13 vs. 18 minutes, respectively, P=.003). For 16 patients who received tPA in MSTUs, the mean door-to-needle time was 26 minutes faster than the control group (32 minutes vs. 58 minutes, P<.001).22

While mobile stroke treatment demonstrates promise for improving early thrombolysis in acute ischemic stroke, there are financial barriers limiting operational feasibility at this time, with annual net costs estimated at about $1.05 million per year.23 One analysis concluded that while the cost-effectiveness of mobile stroke treatment is high, benefit-cost ratios vary based on the travel distance and population density.24 There may be ethical considerations if high costs affect availability, thereby limiting the number of patients who receive care.

Serum Biomarkers

Research shows potential for serum biomarkers in identifying stroke and/or differentiating ischemic and hemorrhagic stroke etiology. The most significantly studied serum stroke biomarkers to date are glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1).25-28 GFAP is an astrocytic intermediate filament protein, specifically found in brain tissue. UCH-L1is an enzyme found in the central nervous system with functions related to neuronal repair after cellular injury.

In a recent study, median serum levels of GFAP and UCH-L1 were significantly higher in patients with intracerebral hemorrhage compared to healthy control patients and patients with ischemic stroke.28

Additionally, a serum cut-off of .34ng/mL of GFAP differentiated intracerebral hemorrhage from ischemic stroke with a sensitivity of 61% and specificity of 96%. While serum biomarkers may not replace imaging in stroke diagnosis, they may be valuable for evaluating tPA eligibility and risk of intracerebral hemorrhage in the future.

Conclusion

Rapid stroke evaluation and treatment is already moving from the emergency department into the prehospital realm. Emergency providers will have to be prepared for patients who may have already received imaging and/or treatment prior to arrival. Tele-stroke networks, mobile stroke units, and serum biomarkers are not only the future of emergency medicine, but also perhaps a new standard of care for acute ischemic stroke patients.

References

  1. Centers for Disease Control, National Center for Health Statistics. Deaths and Mortality. http://www.cdc.gov/nchs/fastats/deaths.htm.
  2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association.Circulation. 2015;131(4):e29-322.
  3. Saver JL. Time is brain–quantified. Stroke. 2006;37(1):263-266.
  4. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med.1995;333:1581-1587.
  5. Abdullah AR, Smith EE, Biddinger PD, Kalenderian D, Schwamm LH. Advance hospital notification by EMS in acute stroke is associated with shorter door-to-computed tomography time and increased likelihood of administration of tissue-plasminogen activator. Prehosp Emerg Care. 2008;12(4):426–431.
  6. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
  7. Fonarow GC, Smith EE, Saver JL, et al. Improving door-to-needle times in acute ischemic stroke the design and rationale for the American Heart Association/American Stroke Association’s target: stroke initiative. Stroke. 2011;42(10):2983-2989.
  8. Fonarow GC, Zhao X, Smith EE, et al. Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA. 2014;311(16):1632-1640.
  9. Tong D, Reeves MJ, Hernandez AF, et al. Times From Symptom Onset to Hospital Arrival in the Get With The Guidelines–Stroke Program 2002 to 2009: Temporal Trends and Implications. Stroke. 2012;43:1912-1917.
  10. Reeves MJ1, Arora S, Broderick JP, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36(6): 1232-1240.
  11. Albright KC, Branas CC, Meyer BC, et al. ACCESS: acute cerebrovascular care in emergency stroke systems. Arch Neurol. 2010;67(10):1210–1218.
  12. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J. Online first. doi doi:10.1136/emermed-2015-205197.
  13. Alberts MJ, Latchaw RE, Jagoda A, et al. Revised and Updated Recommendations for the Establishment of Primary Stroke Centers A Summary Statement From the Brain Attack Coalition. Stroke. 2011;42(9):2651-2665.
  14. Chapman Smith SN, Govindarajan P, Padrick MM, et al: A low-cost, tablet-based option for prehospital neurologic assessment: The iTREAT Study. Neurology. 2016;87:1-8.
  15. Wu TC, Nguyen C, Ankrom C, et al. Prehospital utility of rapid stroke evaluation using in-ambulance telemedicine: a pilot feasibility study. Stroke. 2014;45(8):2342-7.
  16. Lee VH, Cutting S, Song SY, et al. Participation in a Tele-stroke Program Improves Timeliness of Intravenous Thrombolysis Delivery. Telemedicine and e-Health. June 2016, ahead of print.
  17. Schwamm LH, Holloway RG. A review of the evidence for the use of telemedicine within stroke systems of care: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2009;40(7):2626–2634.
  18. Centers for Disease Control and Prevention. A study of primary stroke center policy: Recommendations for policy implementation. Atlanta: U.S. Department of Health and Human Services; 2012.
  19. APPROVED: Acute Stroke–Ready Hospital Advanced Certification Program. Joint Commission Perspectives. 35(2), 2015.
  20. Ebinger M, Kunz A, Wendt M, et al. Effects of Golden Hour Thrombolysis–A Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke (PHANTOM-S) Substudy. JAMA Neurol. 2015;72(1):25-30.
  21. Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA. 2014;311(16):1622-1631.
  22. Itrat A, Taqui A, Cerejo R, et al. Telemedicine in Prehospital Stroke Evaluation and Thrombolysis: Taking Stroke Treatment to the Doorstep. JAMA Neurol. 2016;73(2):162-168.
  23. Hansen-Gyrd D, Olsen KR, Bollweg K, Kronbord C, Ebinger M, Audebert HJ. Cost effectiveness estimate of prehospital thrombolysis—Results of the PHANTOM-S Study. Neurology. 2015;84(11):1090-1107.
  24. 24.Dietrich M, Walter S, Ragoschke-Schumm A, et al. Is Prehospital Treatment of Acute Stroke too Expensive? An Economic Evaluation Based on the First Trial. Cerebrovasc Dis. 2014;38:457-463.
  25. Foerch C, Curdt I, Yan B, et al. Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke. J Neurol Neurosurg Psychiatry. 2006;77(2):181–184.
  26. Foerch C, Niessner M, Back T, et al. Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clin Chem. 2012;58(1):237–245.
  27. Ren C, Zoltewicz S, Guingab-Cagmat J, et al. Different expression of ubiquitin C-terminal hydrolase-L1 and αII-spectrin in ischemic and hemorrhagic stroke: Potential biomarkers in diagnosis. Brain Res. 2013;1540:84-91.
  28. Ren C, Kobeissy F, Alawieh A, et al. Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients. Scientific Reports. 2016;6:24588:1-9.
John Ramos, MMS, PA-C

John Ramos, MMS, PA-C

Resident Physician Assistant, UCSF-Fresno, Fresno, CA
John Ramos, MMS, PA-C

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