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Acute Treatment of Ischemic Stroke

2000; Karger Publishers; Volume: 10; Issue: Suppl. 3 Linguagem: Inglês

10.1159/000047578

1421-9786

Werner Hacke, Markku Kaste, Tom Skyhøj Olsen, Julien Bogousslavsky, Jean‐Marc Orgogozo,

Stroke Rehabilitation and Recovery

Although treatment of risk factors and secondary prevention are helpful with regard to preventing first or new stroke, they continue to happen. It has been shown in several settings that acute treatment of stroke, especially in stroke units, definitely improves outcome and lowers mortality after stroke [Stroke Units Trialists' Collaboration, 1997]. There are four main areas in the treatment of acute stroke. The first one is the treatment of general physiological conditions that need to become optimised in the setting of an acute stroke. This is usually referred to as 'general therapy'. The second is the specific therapy that is directed against different aspects of stroke pathogenesis. Since stroke is mainly caused by acute local or embolic vascular occlusion, one of these aspects is re-canalisation. Another approach aims at the neuronal injury that happens after brain ischaemia, generally referred to as neuroprotection, an area, for which we do not yet have strong evidence that it works. The third main area of stroke treatment is prophylaxis and treatment of complications, which may be either neurological (such as secondary haemorrhage, space-occupying oedema or seizures) or medical (such as infections, decubital ulcers or pulmonary embolism). All these aspects of acute stroke treatment will be covered in this article. The fourth area, early rehabilitation, has already been covered in the first article of this series of recommendations.If a patient arrives at the ward, the key questions to be answered are: 1 Is it a stroke? 2 Is there a life-threatening concomitant disease? 3 What kind of stroke is this? 4 Where in the brain is it? 5 What is the aetiology (is it likely to be arteriosclerosis related, cardio-embolic, haemodynamic or are there small vessel lesions? 6 How dangerous is the stroke (are there signs of poor prognosis)?An initial idea about stroke aetiology is derived from the neurovascular examination, which focuses on the neck vessels, the intracranial vessels, and the heart. Stroke severity and prognosis in ischaemic stroke are, in general, correlated with the severity of the neurologic deficit and the presence or absence of very early ischaemic changes on the initial CT scan. Dense hemiplegia, forced eye deviation and decreased level of consciousness predict poor outcome.Patients with an acute stroke cannot be managed in institutions not meeting the basic requirements detailed in the first article of these recommendations. They should be transferred to a qualified hospital immediately after basic assessment and stabilization of vital functions.There is no fixed sequence of how the different methods should be used. Usually, after blood tests have been ordered, the first test will be (cranial) computerized tomography (CT). This test is needed to establish the differential diagnosis between an intracerebral haemorrhage (ICH) and acute ischaemic stroke. In addition, other intracranial pathologies such as an abscess, an apoplectic glioma, encephalitis, sinus venous thrombosis and occasionally unexpected subarachnoid haemorrhage will be identified using CT. However, just the physical presence of a CT scanner is not sufficient. Expertise in the assessment of subtile early infarctions may be essential not only for identification of patients who may be treated with thrombolytics, but also for patients with bad prognosis and risk of secondary haemorrhage and herniation. In some instances, especially if an expert Doppler study can be performed without delay, it can be done prior to CT scan. Magnetic resonance imaging (MRI) has not yet become part of a routine assessment of the acute stroke patient. Modern sequences capable to visualise vessels (MR angiography), to estimate brain perfusion (perfusion-weighted MR) or to assess early cytotoxic oedema (diffusion-weighted imaging) may in the future play an important role in early stroke management.In all stroke patients, neurological status and vital functions (blood pressure, pulse rate, temperature) should be continuously or discontinuously monitored. Neurological status is best monitored using validated scales/subscales. In selected cases with pre-existing cardiac disease, history of arrhythmias and unstable blood pressure, on-line ECG monitoring is desirable. The electrodes for cardiac monitoring can also be used for respiratory monitoring. Respiratory action is checked clinically if there is no continuous monitoring. Blood pressure monitoring can be performed discontinuously using repetitive automatic inflatable sphygmomanometry or with a mobile 24-hour blood pressure monitoring device. Most of the times, conventional blood pressure monitoring is adequate. Pulse oxymetry is frequently used for continuous monitoring in stroke units. It provides relevant information on the patient's respiratory status. A central catheter and occasionally central venous pressure monitoring is needed for patients with severe stroke treated in specialised wards. Via a central venous catheter, indirect information on intravascular volume, cardiac function and compliance within the venous system can be gained.In most stroke patients, the acute neurologic symptoms are prominent, but treatment and prognosis are co-determined by the underlying and associated systemic diseases that are almost always present. The early discovery and treatment of systemic problems can help prevent later complications. The term 'general treatment' refers to treatment strategies, which are not exclusive to stroke treatment. It rather describes what has to be done for every ill patient in order to provide an optimum physiological basis upon which specific therapeutic treatment strategies can be built [Hacke et al., 1995; Brott et al., 1994]. There is consensus that management of general (internal medical) problems is the basis for stroke treatment [WHO Tasks Force on Stroke and Other Cerebrovascular Disorders, 1989; Brott and Reed, 1989; Adams et al., 1994; The European Ad Hoc Consensus Group, 1996]. General management of stroke patients comprises respiratory and cardiac care, fluid and metabolic management, blood pressure control and perhaps treatment of elevated intracranial pressure. In addition, treatment of seizures and prophylactic measures concerning deep venous thrombosis (DVT), pulmonary embolism, aspiration pneumonia, other infections and decubital ulcer are part of the general treatment of the patients [The European Ad Hoc Consensus Group, 1996, 1997, 1998].Most authors agree that adequate treatment and preservation of vital functions constitute the basis of all therapeutic measures in acute stroke, not only in stroke units, but also in normal wards. On the other hand, one has to keep in mind that even the proposed management of hypertension, hyperglycaemia or fever in stroke patients has never been tested prospectively. It makes sense to keep the patient's general condition in the best physiological shape possible, but in the past, even this has been controversial, as one can see in the changing attitude towards treatment of elevated blood pressure [Einhäupl et al., 1999; Adams et al., 1994; Barsan et al., 1989].Like in the ER, adequate blood oxygenation with normal respiratory function is required for stroke management, although there is no convincing prospective clinical evidence that oxygen supply at low flow rates is useful in human brain infarction. Adequate oxygenation and hyperventilation are without effect on a structurally damaged ischaemic region, but they may be important for the preservation of metabolic turnover in the marginal zone of the insult, the so-called penumbra.A threatened airway may be found in patients with severe pneumonia, heart failure, extensive vertebrobasilar or hemispheric infarction, with large intracranial haemorrhages or with patients with sustained seizure activity following hemispheric stroke. Overt pulmonary dysfunction is occasionally present in the form of slightly exacerbated chronic obstructive airway disease. Some patients develop early AV shunts and require oxygen or even intubation and ventilation. Blood gas analysis (BGA) or an expiratory pCO2 and transcutaneous O2 assessment should be performed early in selected patients with either severe stroke or impaired pulmonary function. Ventilation may be particularly compromised during sleep. Continuous transdermal pulse oxymetry may provide useful information; however, peripheral oxygen saturation of 90% or higher does not necessarily reflect the situation within the brain, particularly within the deep white matter. The oxygenation of the blood is improved by the administration of 2–4 liters O2/min via a nasal tube, and by the use of bronchospasmolytics.If there is no pathological respiratory pattern, and the BGA reveals only moderate hypoxaemia, the administration of oxygen is probably sufficient. In the event of a pathological respiratory pattern, severe hypoxaemia or hypercarbia, and for the unconscious patient at high risk for aspiration, early endotracheal intubation is recommended. In the past, many neurologists did not consider stroke patients candidates for intubation and ventilation, except for those electively intubated for angiography or operation. This attitude is changing. Of course, before intubation is performed, the general prognosis, co-existing life-threatening medical conditions and the presumed will of the patient and his family have to be taken into account. On the other hand, prognosis of stroke patients undergoing intubation is not as bad as reported previously [Grotta et al., 1995] with a 1-year survival rate of about one third of the patients [Steiner et al., 1997]. Prophylactic measures against aspiration have to be taken immediatley. Patients with swallowing disturbances and impaired brain stem reflexes should receive a gastric tube early.Cardiac arrhythmias secondary to stroke are not unusual. Significant alterations in the ST segments and the T waves on the ECG may appear in the acute phase mimicking myocardial ischaemia [Norris, 1983], and cardiac enzymes may be elevated after stroke [Kaste et al., 1978]. Every stroke patient should have an initial ECG. If this is normal, usually no continuous ECG monitoring is required. However, patients with major stroke syndromes and some haemodynamic instability should be continuously monitored and be transmitted to a facility where monitoring can be continued [Furlan, 1987].Subsequently, the intravascular volume must be kept stable. Among the inotropic agents, dobutamine has the advantage of increasing cardiac output without substantially affecting either heart rate or blood pressure. Dopamine may be particularly useful in patients with hypotension or renal insufficiency, and may be combined with a relatively low dosage. Augmentation of cardiac output can increase regional cerebral blood flow (CBF). Increases in cardiac output may increase cerebral perfusion in areas which have lost their autoregulative capacity after acute ischaemia.Not all cardiac phenomena after cerebral ischaemia should be regarded as secondary. There is a coincidence of myocardial infarction, sometimes not particularly clinically impressive, with cerebral ischaemia [Kaste et al., 1978; Furlan, 1987]. use of digitalis is only reasonable when there are obvious signs of myocardial insufficiency. Restoration of normal rhythm by using drugs, cardioversion, or pacemaker care should be performed in co-operation with internists or cardiologists. Optimising cardiac output with maintenance of a high normal blood pressure and a normal heart rate is the essential basis of stroke management. The CVP should be maintained at approximately 8–10 cm H2O, and its monitoring, although not frequently used in a normal ward, will give early warning of a volume deficiency or volume overload, which both have negative effects on cerebral perfusion.Blood pressure monitoring and treatment is a critical issue. In contrast to the old concept that blood pressure reduction should be performed routinely in every acute stroke patient, the treatment of hypertension for good reasons is currently less aggressive. Many patients with acute infarcts have elevated blood pressure. Furthermore, CBF autoregulation may be defective in an area of evolving infarction so that flow in the critical penumbar zone is passively dependent on the mean arterial pressure (MAP). Ischaemia/infarction implies a mismatch between blood flow and the metabolic needs of brain tissue. Hence, maintenance of CBF above the infarction threshold is critical in preventing irreversible brain damage. Normal average CBF is approximately 55 ml/100 g/min. In normal individuals, CBF is constant at a MAP of approximately 80–140 mm Hg. Drops in blood pressure must be avoided if an adequate cerebral perfusion pressure (CPP) is to be maintained. A target systolic blood pressure of 180 mm Hg and diastolic blood pressure of 100–105 mm Hg is recommended for patients with prior hypertension. In other cases, mild hypertension is desirable (160–180/90–100 mm Hg). From those considerations, a high blood pressure is desirable after an ischaemic event. Obviously, this does not apply to extremely high blood pressure levels. Systolic values over 220 mm Hg or diastolic values over 120 mm Hg (in some centres, especially in North America, thresholds of 240 systolic and 130 diastolic are accepted) constitute an indication for early drug treatment, but even here, the reduction in blood pressure should not be too drastic.There are only few indications for immediate antihypertensive therapy in the first hour after symptom onset. Treatment may be appropriate in the setting of acute myocardial ischaemia (although extreme lowering of blood pressure is negative for MI patients too), cardiac insufficiency, acute renal failure or acute hypertensive encephalopathy. After the CT scan has shown a non-ischaemic cause of stroke, such as subarachnoid haemorrhage (SAH), ICH, or epidural or subdural haematoma, antihypertensive treatment may also be started. In ischaemic stroke, antihypertensive therapy administered in the first hour may be dangerous because drops in MAP directly reduce local CBF within the area of infarction. In addition, in stroke patients, the autoregulatory curve is often shifted to the right, i.e. higher levels, because of chronic hypertension. Pharmacologic effects superimposed upon a spontaneous blood pressure decline could result in a hypotensive state. Characteristics of substances used for treatment of hypertension in acute stroke are summarised in tables 1 and 2. Sublingual high doses of calcium antagonists should be avoided because of the risk of overshoot hypertension. Oral and intravenous administration are still frequently used in Europe, although the effects of oral nifedipine are frequently quite substantial, rapid and excessive. The same is true for subcutaneous clonidine. In both cases, the duration of action is hard to predict. Oral captopril (6.25–12.5 mg) has been recommended as an oral first-line drug [Ringleb et al., 1998]. In North America, intravenous labetalol (10 mg), which is available everywhere in Europe, or enalapril are frequently recommended. Excess bradycardia and reduced cardiac output are rare events after labetalol. Increasingly intravenous urapidil is used. Sodium nitroprusside will sometimes become necessary despite some major side effects, which include reflex tachycardia and coronary artery ischaemia. For isolated elevation of diastolic blood pressure, nitroglycerine (in Europe) and sodium nitroprusside (in North America) are frequently used, although both are said to increase intracranial pressure (ICP).Many stroke patients are diabetics. Sometimes diabetes mellitus is discovered for the first time after an ischaemic infarct has developed. A pre-existing diabetic metabolic derangement may be dramatically worsened in the acute phase of stroke, and temporary insulin treatment may become necessary. High glucose levels are not advantageous in stroke [Pulsinelli et al., 1983].A blood glucose level of 200 mg/dl or 10 mmol/l and higher requires immediate insulin titration. Unless the blood glucose level is known, no carbohydrate concentration should be given to a stroke patient.Hypoglycaemia can rarely mimic an acute ischaemic infarction, and its focal signs are not always those of a seizure. On the other hand, hypoglycaemia should be directly antagonized by infusion of 10–20% glucose, preferably via a central venous line.Fever negatively influences neurological outcome after stroke [Castillo et al., 1998; Reith et al., 1996]. Infection is a risk factor for stroke [Syrjanen et al., 1988], and many patients develop an infection after stroke [Grau et al., 1995]. Experimentally, fever increases infarct size. Although there are no controlled trials to support this, it seems to be sensible to treat an elevated temperature in stroke patients. Antipyretics such as Paracetamol and the early use of antibiotics in cases of apparent bacterial infection such as urinary tract infection or aspiration pneumonia are usually recommended. Although there are no prospective data, one may consider lowering body temperature as soon as it reaches 37.5°C.Stroke patients should have a balanced fluid and electrolyte status to avoid plasma volume contraction, raised haematocrit and impairment of rheologic properties of the blood ('sludging'). In the presence of raised intracerebral pressure, a slightly negative fluid balance (about 300– 500 ml negative balance daily) is usually recommended. The electrolytes should be monitored daily and substituted accordingly. If insulin is administered intravenously, consideration should be given to an increased potassium requirement. Uncontrolled volume replacement may lead to pulmonary oedema and cardiac decompensation, and increase cerebral oedema. An intravenous access is needed for initial fluid management and blood draws. If larger volumes of fluids need to be replaced, solutions with high osmolality are used, or if they are substances that may irritate the venous vessel, placement of a central venous catheter is recommended. Central venous lines allow the infusion of high volumes and high concentrations of electrolytes, provided that continuous ECG monitoring is available.Serious electrolyte abnormalities are rare in stroke. In the further course hyponatraemia may occur due to inadequate antidiuretic hormone secretion (IADH syndrome) or due to excess release of atrial natriuretic factor (ANF) [Diringer et al., 1988]. IADH is managed by fluid restriction or hypertonic saline, whereas normovolaemia should be maintained if excess ANF is suspected [Diringer et al., 1988].Recommendations 1 Patients should be treated in a stroke unit (level I). 2 Neurological status and vital functions should be monitored regularly. 3 Secure airways and provide adequate oxygenation. 4 Do not treat hypertension in the first phase after stroke if there are no extremely high values or internal indication. 5 Monitor glucose and body temperature and correct them if elevated. 6 Close monitoring and correction of electrolyte disturbances is advised.None of the recommendations concerning general treatment has been verified in placebo-controlled, randomised, blinded studies. However, the proven efficacy of stroke units to some extent may be caused by adherence to guidelines for general treatment, which may be used as an indirect proof of efficacy of general treatment procedures.Thrombolytic therapy with rtPA (0.9 mg/kg body weight) given within 3 h after stroke onset to patients with acute ischaemic stroke significantly improves outcome after stroke [The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, NINDS, 1995]. This treatment is not yet approved in Europe, while it is in North America. There is evidence that thrombolysis may also work up to 6 h after stroke onset in carefully identified patients [Hacke et al., 1998, Wardlaw and Warlow, 1999]. The results of ATLANTIS, a 3- to 5-hour randomised rt-PA trial did not show any effects on outcome or mortality [Albers et al., 1999]. This therapy is not undisputed. In Europe, there is still some doubt about its risk benefit ratio, which prevents some centres from actively promoting it. Caution is advised before giving intravenous rtPA to persons with severe stroke (NIH stroke scale >22), or if the CT demonstrates extended early changes of a major infarction, such as sulcal effacement, mass effect and oedema. In centres where thrombolytic therapy is offered, it should only be given if the diagnosis is established by a physician who has expertise in the diagnosis of stroke, and a CT of the brain is assessed by physicians who have expertise in reading this imaging study. Because the use of thrombolytic drugs carries the real risk of major bleeding, the risks and potential benefits of rtPA should be discussed whenever possible with the patient and family before treatment is initiated. A recent meta-analysis of all randomised rtPA trials demonstrates an increase in independent patients without increased morbidity or mortality [Wardlaw and Warlow, 1999]. According to the Cochrane reviewers, thrombolysis in acute ischaemic stroke seems to be increasingly robust within 3 and possibly 6 h of stroke. However, the Cochrane reviewers still consider the number of patients randomised to be too small, so that there is little evidence on which subgroups of stroke might particularly benefit or be harmed, and hence not enough evidence to draw final conclusions about the effect of thrombolytic drugs in acute stroke. Intravenous administration of rtPA more than 3 h after stroke should only be given in an institutional protocol as experimental therapy.Intravenous streptokinase has been shown to be associated with an unacceptable risk of haemorrhage and haemorrhage-associated death [The Multicenter Acute Stroke Trial – Europe Study Group, 1996; Donnan et al., 1995].Intra-arterial thrombolytic therapy of occlusions of the proximal part of the middle cerebral artery, using pro-urokinase, has been shown to be significantly associated with better outcome in a recently published randomised trial. This treatment requires superselective angiography and is only available in selected centres [Furlan et al., 1999]. The treatment is safe and efficacious in a 6-hour time window.Intra-arterial treatment of acute basilar occlusion with urokinase or rtPA is frequently used in selected centres, but has not been subjected to a randomised trial [Hacke et al., 1988; Brandt et al., 1996].Recommendations for Centres Offering Thrombolysis 1 Intravenous rtPA (0.9 mg/kg; maximum 90 mg), with 10% of the dose given as a bolus followed by an infusion lasting 60 min, is the recommended treatment within 3 h of onset of ischaemic stroke (level I). 2 The benefit from the use of intravenous rtPA for acute ischaemic stroke beyond 3 h after onset of the symptoms is smaller, but present in selected patients (level I). 3 Intravenous rtPA is not recommended when the time of onset of stroke cannot be ascertained reliably; this includes persons whose strokes are recognised upon awakening (level III). 4 Intravenous administration of streptokinase, outside the setting of a clinical investigation, is dangerous and not indicated for the management of persons with ischaemic stroke (level I). 5 Data on the efficacy or safety of any other intravenously administered thrombolytic drugs are not available to provide a recommendation. 6 Intra-arterial treatment of acute middle cerebral artery occlusion in a 6-hour time window using pro-urokinase results in a significantly improved outcome (level I). 7 Acute basilar occlusion may be treated with intra-arterial therapy in selected centres (level IV).Ancrod, a defibrinogenating enzyme has been shown to improve outcome after acute ischaemic stroke if given within 3 h after stroke onset and over 5 days [Sherman, for the STAT Writers Group, 1999]. Recently, a European trial testing ancrod treatment in a 6-hour time window has been terminated prematurely.Recommendation 1 Ancrod given in a 3-hour time window significantly improves outcome after acute ischaemic stroke (level I).The results of two very large randomised, non-blinded intervention studies indicate that aspirin given within 48 h after stroke (IST, CAST) seem to reduce mortality and rate of recurrent stroke minimally, but statistically significantly [International Stroke Trial Collaborative Group, 1997; Chinese Acute Stroke Trial, 1997]. Whether the mild positive effect of early aspirin is due to an effect on the infarct itself or due to prevention of recurrent infarction is not yet clear. It may be discussed that the NTN anti-inflammatory effect of aspirin may also influence the overall result.Early anticoagulation has been used frequently in treatment after acute ischaemic stroke. Unfortunately, none of the trials that have been performed in the past years has supported the idea that early heparin may influence outcome after ischaemic stroke or at least may reduce the number of recurrent strokes. Several studies that used intravenous heparinoids [The TOAST Publication Committee, 1998], subcutaneous low-molecular-weight heparin [Kay et al., 1995; Hommel et al., 1998] or subcutaneous heparin [Internationl Stroke Trial Collaborative Group, 1997] failed to show an overall benefit of treatment [Swanson, 1999]. While there was some kind of improvement in outcome or reduction in stroke recurrence rates, this was almost always counterbalanced by an increased number of haemorrhagic complications. In the past 10 years, no randomised studies have been performed to test the effects of early full anticoagulation with conventional heparin following acute ischaemic stroke, which is still used frequently in many centres. In addition, many investigators believe that heparin is not and never will be a standard therapy for all stroke subtypes. However, they believe that high-risk patients (such as patients with stroke associated with atrial fibrillation, for example) should be studied separately [Chamorro et al., 1999]. Such a study is not available right now, and therefore, the remaining indictions for the use of acute heparin after ischaemic stroke are not evidence based. Table 3 gives some indications as to when full-dose intravenous heparin may currently still be proposed.Usually it is recommended to elevate the partial thromboplastin time up to twice the individual baseline. Heparin should only be given as long as it takes to decide on the appropriate secondary prevention. Contra-indications for the treatment with heparin include large infarcts (e.g. more than 50% of MCA territory), uncontrollable arterial hypertension and advanced microvascular changes in the brain.Isovolaemic haemodilution that lowers the haematocrit by 15% or more results in reductions in blood viscosity and improvements in CBF. Several large clinical trials of isovolaemic haemodilution were unable to demonstrate a decline in mortality of disability with treatment [Strand, 1992; Italian Acute Stroke Study Group, 1988; Scandinavian Stroke Study Group, 1987; The Hemodilution in Stroke Study Group, 1989]. Hypervolaemic haemodilution has been examined in small randomised trials with conflicting results. The clinical benefit of haemodilution therapy has not been established, and the possibility of excess brain oedema has not been excluded.Not a single neuroprotective agent has been shown to influence outcome after stroke. Currently, there is no recommendation to treat patients with neuroprotective drugs after ischaemic stroke.Recommendations 1 There is no recommendation for general use of heparin, low-molecular heparin or heparinoids after ischaemic stroke (level I). 2 Full-dose heparin may be used when there are selected indications such as artrial fibrillation, other cardiac sources with high risk of re-embolism, arterial dissection or high-grade arterial stenosis (level IV). 3 Aspirin (100–300 mg per day) may be given after stroke to an unselected population, even without CT scan (level I). 4 Haemodilution therapy is not presently recommended for the management of patients with acute ischaemic stroke (level I). 5 Currently, there is no recommendation to treat patients with neuroprotective substances of the ischaemic stroke (level I).Acute stroke predisposes to medical complications such as pneumonia, urinary tract infections, malnutrition or volume depletion. Patients may also suffer from DVT and pulmonary embolism. Early supportive care and monitoring of physiological parameters may prevent such complications. This is best done in a dedicated stroke unit with experienced staff and early mobilisation. Immobility may lead to infections, contractions and decubital ulcers.One of the most important risks in the early phase after stroke is aspiration pneumonia. Bacterial pneumonia accounts for 15–25% of stroke deaths [Silver et al., 1984]. The majority of the pneumonias are caused by aspiration [Horner et al., 1988]. Since aspiration may be detectable by video fluoroscopy in as many as 50% of patients during the initial days after stroke onset, oral feeding should be withheld until the patient has demonstrated both intact swallowing with small amounts of water and intact coughing on command. Aspiration is frequently found in patients with reduced consciousness, but also in patients with impaired gag reflexes or with swallowing disturbances, which are not only found after brain stem stroke. Nasogastric feeding may be helpful in the prevention of aspiration pneumonia, although it does not completely reduce the risk. Other reasons for pneumonia include hypostatic pneumonia due to poor caving and immobilization. Frequent changes of the patient position in bed and pulmonary physical therapy may prevent this type of pneumonia.Many stroke patients have swallowing disturbances. This can be tested