Stroke is defined as an acute focal neurological deficit resulting from a cerebrovascular disease. The two main types of stroke are ischemic and hemorrhagic, accounting for approximately 85% and 15%, respectively (Hickey 2003. The clinical practice of neurological and neurosurgical nursing (5th ed.). Philadelphia: Lippincott, Williams & Wilkins). When an ischemic stroke occurs, the blood supply to the brain is interrupted, and brain cells are deprived of glucose and oxygen. Approximately 45% of ischemic strokes are caused by small or large artery thrombus, 20% are embolic origin, and others have an unknown cause (Hickey 2003. The clinical practice of neurological and neurosurgical nursing (5th ed.). Philadelphia: Lippincott, Williams & Wilkins).
Transient ischemic attack (TIA) (also known as “mini-stroke”) is a syndrome characterized by the sudden onset of discrete neurological symptoms that resolve completely within 24 hours. TIA may be reported by 0.5-8% of the elderly population (Bots et al., 1997. Stroke 28(4): 768-73). A patient representing with a TIA is at high risk of subsequent adverse events. The 90-day risk of stroke has been reported to be greater than 10%, with the highest risk occurring within the first 2 days (Jonston et al., 2003. Neurology 60: 1429-34).
Stroke is one of the most important vascular diseases. Stroke remains the second leading cause of death worldwide and is one of the main causes of adult disability and early invalidity in Europe (Murray and Lopez, 1997. Lancet 349: 1269-76; Murray and Lopez 1997. Lancet 349:1498-504). In the US more than 700 000 people have a stroke each year, whereof 550 000 are first strokes (Thom et al. 2006. Heart disease and stroke statistics—2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113: 85-151). Therefore, it is an important public health problem and a burden to health care providers and to the community at large because of the amount of effort that has to be invested in the planning and provision of healthcare.
The incidence of stroke increases markedly with increasing age in our society (Modan and Wagener, 1992. Stroke 23:1230-36). Most ischemic strokes occur between the ages of 71 an 80 years while most hemorrhagic strokes between 60 and 70 years appear (Colombo et al., 1989. Rivista de Neurologia 59: 1-7).
Neuroradiological imaging methods like computer tomography (CT) or magnetic resonance tomography (MRT) are used for diagnosis of stroke. CT scanning is recommended for patients suffering from acute stroke caused by cerebral haemorrhage. This method, however, is less effective in patients suffering from an acute ischemic insult (sensitivity less than 33%). Doppler sonography and digital subtraction angiography (DSA) can additionally be used to determine the causes of acute circulatory disturbances.
Treatment of ischemic stroke is normally focussed on supporting vital functions and on rehabilitative measures. Therapies are aimed at removing the blockage by breaking the clot or by removing it mechanically, minimizing clot enlargement and preventing new clots from forming. Thrombolysis (breakdown of blood clots) can be induced by applying plasminogen activator (tPA or PLAT) within the first 3 hours after the stroke. Since some disease states like hypoglycaemia, migraine, cerebral haemorrhage and certain brain tumours have similar symptoms as acute ischemic stroke, there is a need for rapid differential diagnosis.
Therapy also needs to be adjusted according to the patients individual situation, e.g. the individual prognosis and/or the individual risk of further strokes.
Prognosis of the outcome for stroke patients after a defined interval can either be functional or related to individual survival. For functional outcome prognosis the morbidity of a patient after a defined time is determined using a score system such as the modified Rankin_Scale (mRS; Bonita and Beaglehole, 1988. Modification of Rankin Scale: Recovery of motor function after stroke. Stroke 19: 1497-1500) or the National Institutes of Health Stroke Scale (NIHSS; Adams et al., 1999. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 53: 126-31), the NIHSS currently being the gold standard. The functional outcome may also be expressed in terms of need of nursing care or with respect to activities of daily living (ADL), e.g. according to the Barthel Index and Rankin Scale (Collin et al., 1988. The Barthel ADL Index: a reliability study. International Disability Study 10: 61-3; Bonita and Beaglehole, 1988. Modification of Rankin Scale: Recovery of motor function after stroke. Stroke 19: 1497-1500). Some biomarkers have been reported to be indicative for future cardiovascular events, e.g. a further stroke. Potential stroke biomarkers that have been reported are S-100B (Serum protein 100 Beta; Stranjalis et al. 2007 Acta Neurochir (Wien) 149: 231-7; Foerch et al. 2005. Arch Neurol 62: 1130-4), NSE (neuronenspezifische Enolase; Anand and Staed 2005. Cerebrovasc Dis 20: 213-9), GFAP (glial fibrillary acidic protein; Nylen et al., 2007. Stroke 38: 1489-94), CRP (C-reactive protein; Di Napoli et al. 2001. Stroke 32: 133-8; Di Napoli et al. 2001. Stroke 32: 917-24), IL-6 (Interleukin-6; Orion et al. 2008. Eur J Neurol 15:323-8; Shenhar-Tsarfaty et al., 2007. Thromb Res 122:167-73), and Plasma-Fibrinogen (Turaj et al. 2006. J Neurol Sci 246: 13-9).
N-terminal proBNP (NT-proBNP) has been shown to be an independent variable for individual survival prognosis after an ischemic stroke (Jensen et al. 2006. Cerebrovasc Dis 22: 439-44; Sharma et al. 2006. J Stroke Cerebrovasc Dis 15: 121-7; Mäkikallio et al. 2005. Stroke 36: 1016-20; Yip et al. 2006. Circ J 70: 447-52) and after an hemorrhagic stroke (Sharma et al. 2006. J Stroke Cerebrovasc Dis 15: 121-7).
The levels of mature ANP (Estrada et al. 1994. Am J Hypertens 7: 1085-9) and ADM (Hosomi et al. 2004. J Hypertens 22: 1945-51) have been determined in samples of patients with ischemic stroke. However, no correlation of the ANP concentrations with the neurological status (Mathew's modified scale) or outcome could be shown.
Elevated ET-1 concentrations have been found in the blood of stroke patients without investigating the prognostic value of these data (Ziv et al. 1992 Stroke 23: 1014-6; Alioglu et al. 2002. Angiology 53: 77-82; Giannopoulos et al. 2008. Neurol. Res. 30(7):727-30). ET-1 levels have been found to be elevated in patients after an ischemic stroke (Estrada et al. 1994. Am J Hypertens 7: 1085-9) but no correlation with the rate of survival has been determined.
An investigation of the serum Procalcitonin (PCT) levels of patients suffering from an acute stroke (Miyakis et al. 2004. Clin Chim Acta 350: 437-9) did not reveal significant differences of the levels at the day of hospitalization and day 7. No correlation of the PCT levels with mortality or neurological outcome has been found in this study.
Human growth hormone (hGH) is a polypeptide produced by the somatotrope cells in the pituitary. It is secreted in a pulsatile fashion (10 to 20 pulses in each 24-hour cycle) and its secretion is regulated by three hypothalamic peptides, growth hormone releasing hormone (GHRH) and ghrelin, which stimulate hGH secretion, and somatostatin, which inhibits hGH secretion by back regulation (Kato et al. 2002. Regulation of human growth hormone secretion and its disorders. Internal Med 41: 7-13).
HGH is heterogenous, consisting of several molecular isoforms and fragments (Baumann G. 1991. Growth hormone heterogeneity: genes, isohormones, variants and binding proteins. Endocr Rev 12: 424-449). Four major isoforms of hGH have been identified in the human pituitary ranging in the amino acid number and include 191 aa (frequency of 87.5%), 176 aa (8.1%), 153 aa (3.3%) and 145 aa (11%) (Zhan X. et al. 2005. Proteomics analysis of growth hormone isoforms in the human pituitary. Proteomics 5: 1228-41). The 191 aa form has a molecular weight of 22 kDa and is co-secreted from the anterior pituitary gland with the 176 aa form (20 kDa isoform), lacking the amino acid residues 32 to 46 (De Palo E. et al. 2006. Growth hormone isoforms and segments/fragments: molecular structure and laboratory measurements. Clin Chim Acta 365: 67-76).
The secretion of hGH is slightly higher in women than in men, with the highest levels observed at puberty. Secretion decreases with age by around 14% per decade. Moreover secretion varies with normal physiological and pathophysiological conditions. The principal physiological regulation mechanisms of hGH secretion are neural endogenous rhythm, sleep, stress, exercise, and nutritional and metabolic signals: hGH levels are higher during slow wave sleep (typically one to two hours after falling asleep) and are increased by exercise, stress, fever, fasting and with some amino acids (leucine and arginin). HGH secretion is also stimulated by insulin-induced hypoglycaemia, L-dopa, clonidine (α2-adrenergic agonist), γ-hydroxybutyrate and β-adrenergic blocking agents, whereas oral administration of glucose and increased serum free fatty acid levels rather suppress hGH secretion. hGH secretion is also blunted in obesity and by aging. (Review in: Kato et al. 2002. Regulation of human growth hormone secretion and its disorders. Internal Med 41: 7-13).
C-reactive protein (CRP) is a plasma protein that was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C polysaccharide of pneumococcus. Patients with elevated basal levels of CRP have been shown to have an increased risk for diabetes, hypertension and cardiovascular disease (Pradhan et al. (2001. JAMA 286: 327-334; Dehghan. 2007, Diabetes 56: 872).
Troponin is a complex of three regulatory proteins that is integral to muscle contraction in skeletal and cardiac muscle, but not smooth muscle. Troponin has three subunits: TnC, TnI, and TnT. Individual subunits serve different functions: Troponin C (TnC) binds to calcium ions to produce a conformational change in TnI. Troponin T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex. Troponin I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place. Certain subtypes of troponin (cardiac troponin I and T) are very sensitive and specific indicators of damage to the heart muscle (myocardium). Their level in blood samples can be used to differentiate between unstable angina and myocardial infarction (heart attack) in patients with chest pain (Antman et al. 1996. N Engl J Med; 335:1342-9).