Worldwide, stroke is second only to coronary artery disease as a cause of death, and is the leading cause of disability in the USA. In total, 88% of these events are ischemic strokes, and 8–12% of these ischemic strokes result in death within 30 days Citation[1].
The stroke-themed sections of Expert Review of Neurotherapeutics, which are featured in the journal every February and August, offer valuable insights into a number of transdisciplinary and practical issues in selective aspects of vascular diseases of the CNS. In this issue, a detailed comparative study of different service configurations on the delivery of intravenous thrombolysis in acute ischemic stroke, a discussion of advances in the management of lacunar strokes and a management update on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are covered in detail.
Systematic review of stroke thrombolysis service configuration
Effective specialized acute stroke management requires expert, rigorous application of evidence-based data when available, transdisciplinary collaboration and optimal coordination. Thrombolysis with intravenous tissue plasminogen activator is currently licensed for treatment of acute ischemic stroke within 3 h of onset. Although approximately a third of patients present to hospital within this time window, only a very small fraction are currently treated with thrombolysis Citation[2–4]. Therefore, new models of intervention are needed to handle the hyperacute phase of the diagnosis and treatment of acute stroke events in ‘real-life settings’. Improving communication between key components involved in the delivery of a stroke care system is essential to maximize the number of appropriate patients administered hyperacute stroke therapy.
Telemedicine, an important and rapidly evolving concept, potentially offers such a framework by increasing the availability of subspecialty expertise to remote geographic areas in an efficient manner. Telemedicine for stroke, ‘telestroke’, represents a potential time-saving means for evaluating and managing acute ischemic stroke and has been effectively utilized in some European countries. In an increasingly globalized world, acceptance and outsourcing of telemedicine (e.g., teleradiology) service systems into practice is a reality. Journals of telemedicine and telecare are available. Teleradiology has also been used extensively by the military in the Balkans, Afghanistan and Iraq. Pan-European teleradiology projects are underway and many hospitals across the country are currently outsourcing radiology services, among others Citation[5–7].
As the concept and discipline of telestroke develops further, more robust data on its feasibility will be needed. A number of medical–legal frameworks, within which the concept of telestroke can be developed, will require clear regulations and answers, including coverage of out-of-state security aspects of tele-equipments, retention of records, service agreements, patient satisfaction and reimbursement issues, among others.
Lacunar stroke
In the USA, approximately 600,000 people experience a first occurrence of stroke each year, and an additional 180,000 experience recurrent events Citation[8]. Of these events, approximately 87% are ischemic in origin Citation[8]. Ischemic strokes can be attributed to large-vessel atherothrombosis, small-artery disease (lacunes), cardioembolism, aorto-embolism, nonatherosclerotic vasculopathies or hypercoagulable states, or may be categorized as cryptogenic Citation[8].
Small-vessel or penetrating artery diseases (lacunes) usually occur in patients with longstanding arterial hypertension. Available evidence suggests that structural changes of the cerebral vasculature due to arterial hypertension are characterized by fibrinoid angiopathy, lipohyalinosis and microaneurysm formation Citation[9,10]. Accelerated hypertensive arteriolar damage of the small-diameter penetrating arteries is operative in a large number of patients with lacunar infarction. Microatheroma of the ostium of a penetrating artery, embolism from cardiac, aortic, arterial sources or changes in hemorrheology are pathophysiologically operative in the remainder of cases Citation[11].
Treatment strategies center around the management of modifiable risk factors through a combination of lifestyle modifications, including diet, exercise, smoking cessation, pharmacologic treatment with antihypertensive, antihyperlipidemic and antiplatelet agents, and carotid artery surgery in high-risk patients Citation[12–15]. Without doubt, the risk of bleeding is the most critical aspect for patients undergoing anti-thrombotic treatment. As yet, it is uncertain whether foci of old hemorrhages (microbleeds), often found among patients with small-vessel disease, represent a contraindication for anti-thrombotic therapy or increase risk for the administration of thrombolytic therapy.
CADASIL: management or what to do when there is little one can do
Although CADASIL is a rare disorder, increased recognition of isolated cases and individuals with less-obvious features suggests that CADASIL is still under-recognized. CADASIL is caused by mutations of the Notch 3 gene and is characterized by ultrastructural abnormalities in small cerebral and systemic vessels Citation[16]. Diagnosis can be confirmed with DNA testing or by finding typical eosinophilic material within the basement membrane of vascular smooth muscle cells from a skin biopsy Citation[16]. Abnormalities of vasomotor function in systemic small arteries have been reported among these patients Citation[17].
Specific treatment for CADASIL is not currently available. Control of vascular risk factors and administration of platelet anti-aggregants is a logical approach. Daily calcium channel blockers may be useful for headache prophylaxis. Donepezil, a drug used to treat Alzheimer’s disease, has not been shown to be effective in CADASIL patients Citation[18,19]. Anecdotal reports claim certain benefits for L-arginine Citation[20]. Likewise, others recommend the administration of angiotensin-receptor blockers Citation[21].
Future topics
Future topics of interest that will feature in forthcoming issues of Expert Review of Neurotherapeutics include the modern use of neuroimaging in acute stroke trials, management strategies for cerebral venous thrombosis, recent advances in neuromuscular stimulation of the upper and lower limbs following stroke and the correlation of blood glucose in acute stroke and clinical outcomes.
Use of neuroimaging in acute stroke trials
Imaging strategies in acute stroke require an orderly approach designed to rapidly obtain pertinent anatomical, vascular and functional information. Algorithms vary according to institutional preferences. Some favor an initial, unenhanced computed cranial tomography (CT) to exclude intracranial hemorrhage, since CT is widely available, easy to perform, inexpensive and allows rapid data acquisition. However, it must be emphasized that early parenchymal signs of cerebral ischemia are often subtle using CT. The sequence is then followed by dynamic CT perfusion imaging, which offers an assessment of brain perfusion by measuring parenchymal density changes resulting from the passage of the contrast bolus over time. Subsequently, CT angiography is obtained, which also allows 3D reconstruction of extra- and intracranial blood vessels. However, others favor a different algorithm and, after obtaining an unenhanced CT, proceed with MRI (scout, fluid-attenuated inversion-recovery or gradient-echo and diffusion weighted), extra- and intracranial magnetic resonance angiogram and magnetic resonance perfusion.
Cerebral venous thrombosis
Cerebral venous thrombosis is relatively uncommonaccounting for only approximately 1% of all strokes Citation[22]. Cerebral venous thrombosis is more common in neonates and women Citation[23]. In adults, cerebral venous thrombosis is also more common among young people, although 8% of patients affected with cerebral venous thrombosis are 65 years of age or older Citation[22]. The incidence of cerebral venous thrombosis is apparently higher in India and other Asian countries Citation[24].
Cerebral venous thrombosis may be secondary to, for example: local, regional or systemic infections; genetic or acquired prothrombotic states; a diverse array of hematological conditions; malignancies; inflammatory disorders; pregnancy/puerperium; an ever-expanding list of drugs (e.g., oral contraceptives, hormone-replacement therapy, androgens, tamoxifen and L-asparaginase); head trauma; placement of endovenous catheters; dehydration; or congenital heart diseases Citation[25].
Management strategies focus on anticoagulation, seizure control and management of increased intracranial pressure, removal of the precipitating source, if found, and appropriate antimicrobials in cases with septic etiologies Citation[26]. Endovascular administration of thrombolytic agents into the dural sinuses, in isolation or in combination with mechanical thrombectomy, has been increasingly utilized with promising results Citation[27].
Neuromuscular stimulation for the rehabilitation of the upper & lower limb after stroke: from technology to clinical deployment
A better understanding of how neuromuscular stimulation modifies the interactions within the nervous system and influences motor relearning is needed. The efficacy, measurement validation and therapeutic applications of neuromuscular stimulation in enhancing the upper-extremity motor and functional recovery after stroke has been proposed by many experts Citation[28]. However, many of the published studies had small sample sizes and, thus, no definite conclusions have been reached. Novel neurophysiologic research into the mechanisms of neuromuscular stimulation and large multicenter randomized clinical trials are needed before a widespread adoption of such techniques.
Blood glucose in acute stroke
A total of 6 million Americans have diabetes mellitus, and at least 5 million more people are undiagnosed Citation[29]. Diabetes is associated with a two- to fourfold increased risk of ischemic cerebrovascular disease Citation[30]. It is estimated that at least 25% of all ischemic strokes are related to the effects of diabetes, either alone or in association with arterial hypertension Citation[31]. Patients with diabetes also have more-severe cerebral ischemic events and higher mortality after stroke. Likewise, admission blood glucose predicts increased 28-day case–fatality rate among diabetic and nondiabetic patients with an intracerebral hemorrhage Citation[32]. Furthermore, hyperglycemia may be an important risk factor for hemorrhagic conversion of acute cerebral infarction following the administration of tissue plasminogen activator Citation[32]. Patients with diabetes mellitus also have a higher fatality rate in myocardial infarction than those without diabetes Citation[33].
Admitting hyperglycemia is also common after stroke, and has been associated with increased cerebral lactate and brain tissue acidosis, and short- and long-term mortality Citation[32]. In addition, admission hyperglycemia increases hospital mortality among critically ill patients Citation[32,34]. Hyperglycemia-related decreased survival after acute stroke most likely indicate a ‘stress response’, rather than an indication of pre-existing diabetes mellitus. Finally, stress hyperglycemia has also been associated with poor functional recovery among diabetic and nondiabetic patients after stroke. Robust trials of intensive therapy of hyperglycemia after stroke are needed.
Conclusion
I hope these stroke-themed sections of Expert Review of Neurotherapeutics will continue to offer concise and insightful overviews and a systematic discussion of important aspects in the fast-moving discipline of cerebrovascular diseases. These sections are valuable additions to the current stroke literature and are particularly interesting for physicians in several disciplines caring for these challenging patients.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Carandang R, Seshadri S, Beiser A et al. Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA296(24), 2939–2946 (2006).
- Hacke W, Kaste M, Bluhmki E et al.; ECASS investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med.359(13), 1317–1329 (2008).
- Tsivgoulis G, Alexandrov AV. Timeframe for thrombolysis in acute ischaemic stroke. Lancet372(9646), 1275–1276 (2008).
- Schumacher HC, Bateman BT, Boden-Albala B et al. Use of thrombolysis in acute ischemic stroke: analysis of the Nationwide Inpatient Sample 1999 to 2004. Ann. Emerg. Med.50(2), 99–107 (2007).
- Levine SR, McConnochie KM. Telemedicine for acute stroke: when virtual is as good as reality. Neurology69(9), 819–820 (2007).
- Demaerschalk BM, Miley ML, Kiernan TE et al.; STARR Coinvestigators. Stroke telemedicine. Mayo Clin. Proc.84(1), 53–64 (2009).
- Thrall JH. Teleradiology. Part II. Limitations, risks, and opportunities. Radiology244(2), 325–328 (2007).
- Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol. Clin. (4), 871–895 (2008).
- Taylor WR. Mechanical deformation of the arterial wall in hypertension: a mechanism for vascular pathology. Am. J. Med. Sci.316(3), 156–161 (1998).
- Luepker RV, Arnett DK, Jacobs DR Jr et al. Trends in blood pressure, hypertension control, and stroke mortality: the Minnesota Heart Survey. Am. J. Med.119(1), 42–49 (2006).
- Sacco S, Marini C, Totaro R et al. A population-based study of the incidence and prognosis of lacunar stroke. Neurology66(9), 1335–1338 (2006).
- Schwamm LH, Fonarow GC, Reeves MJ et al. Get with the guidelines-stroke is associated with sustained improvement in care for patients hospitalized with acute stroke or transient ischemic attack. Circulation119(1), 107–115 (2009).
- Adams HP Jr. Secondary prevention of atherothrombotic events after ischemic stroke. Mayo Clin. Proc.84(1), 43–51 (2009).
- Sacco RL, Adams R, Albers G et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation113(10), E409–E449 (2006).
- Gorelick PB. Primary prevention of stroke: impact of healthy lifestyle. Circulation118(9), 904–906 (2008).
- Joutel A, Favrole P, Labauge P et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet358(9298), 2049–2051 (2001).
- Saiki S, Sakai K, Saiki M et al. Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene. Neurology67(2), 337–339 (2006).
- Dichgans M, Markus HS, Salloway S et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol.7(4), 310–318 (2008).
- Schneider LS. Does donepezil improve executive function in patients with CADASIL? Lancet Neurol.7(4), 287–289 (2008).
- Peters N, Freilinger T, Opherk C et al. Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL. J. Neurol.255(8), 1203–1208 (2008).
- Kusaba T, Hatta T, Kimura T et al. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin. Nephrol.67(3), 182–187 (2007).
- Gosk-Bierska I, Wysokinski W, Brown RD Jr et al. Cerebral venous sinus thrombosis: incidence of venous thrombosis recurrence and survival. Neurology67(5), 814–819 (2006).
- Sébire G, Tabarki B, Saunders DE et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain128(Pt 3), 477–489 (2005).
- Khealani BA, Wasay M, Saadah M et al. Cerebral venous thrombosis: a descriptive multicenter study of patients in Pakistan and Middle East. Stroke39(10), 2707–2711 (2008).
- Smith R, Hourihan MD. Investigating suspected cerebral venous thrombosis. Br. Med. J.334(7597), 794–795 (2007).
- Roach ES. Cerebral venous sinus thrombosis: to treat or not to treat? Arch. Neurol.65(7), 987–988 (2008).
- Philips MF, Bagley LJ, Sinson GP et al. Endovascular thrombolysis for symptomatic cerebral venous thrombosis. J. Neurosurg.90(1), 65–71 (1999).
- Hedman LD, Sullivan JE, Hilliard MJ, Brown DM. Neuromuscular electrical stimulation during task-oriented exercise improves arm function for an individual with proximal arm dysfunction after stroke. Am. J. Phys. Med. Rehabil.86(7), 592–596 (2007).
- Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch. Intern. Med.167(9), 921–927 (2007).
- Ripley DL, Seel RT, Macciocchi SN, Schara et al. The impact of diabetes mellitus on stroke acute rehabilitation outcomes. Am. J. Phys. Med. Rehabil.86(9), 754–761 (2007).
- Kittner SJ, White LR, Losonczy KG, Wolf PA, Hebel JR. Black–white differences in stroke incidence in a national sample. The contribution of hypertension and diabetes mellitus. JAMA264(10), 1267–1270 (1990).
- Williams LS, Rotich J, Qi R et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology59(1), 67–71 (2002).
- Worthley MI, Shrive FM, Anderson TJ, Traboulsi M. Prognostic implication of hyperglycemia in myocardial infarction and primary angioplasty. Am. J. Med.120(7), 643.e1–e7 (2007).
- Woo J, Lam CW, Kay R et al. The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch. Neurol.47(11), 1174–1177 (1990).