INTRODUCTION:

Pathophysiology of stroke:

Ischemic stroke is one of the most reasons of death and inability. The pathophysiological changes occur as a result of stroke and can be helpful for a better diagnosis. Normally, cerebral blood flow (CBF) is about 500ml/100gr/min. The blood flow in the gray matter is more than the white matter[1].

When cerebral spinal fluid (CSF) starts to debate, vasodilation occurs and the brain begins to compensate the reduction of blood stockpile by increasing the demand of available glucose and O2. A slight decrease in blood flow and CSF leads to protein consumption and glycolysis because of the lactic acid accumulation and acidosis state, respectively,[1, 2]. The more CSF volume decreases (<200mg/100gr/10min), the less oxidative phosphorylation pathway works properly and the brain cells supply begins to wane [3]. Brain cells would not be able to provide enough energy for the sodium-potassium pumps in their membrane. Therefore, active ones begin to get destructed [1]. The destruction of the pumps leads to indiscriminate exchange of ions on either side of the membrane [3,4]. All these happenings occur a few minutes after the stroke and cause impairment in nervous system. This is called cytotoxic edema, when the explained mechanism happens in an extensive volume[4]. Vasogenic edema fall out 2 hours after the stroke [Ref]. Ischemia leads to endothelial cell destruction and destroys the tight junction of the capillaries and causing a breakdown in the brain blood barrier (BBB) [2,5]. This leads to plasma proteins and water accumulation in extra cellular and intra vascular space [1, 2, 5]. Vasogenic edema which usually occurs 3 to 4 days after the onset of infarction. For its enormous clinical, social, and economic implications, it is urgent to understand the mechanisms and the results of guiding in the diagnosis and treatment the procedures of the stroke[1,4]. Different detection from MRI sequences aid characterizes stroke mechanisms that affect anticipation and could have an essential role in therapy. MRI is able to trusty deprive intracerebral hemorrhage (4,6). Diffusion weighted (DW) and perfusion weighted (PW) in magnetic resonance imaging (MRI) are excellent neuroimaging examinations in management of the stroke patients' biomarkers. These advanced imaging techniques can support a clinical diagnosis of stroke, identify patients at risk, and guide treatment procedures. Hence, applying to these modern diagnostic procedures would be valuable for patient and physician [6]. The purpose of the present study is to evaluate sensitivity of DW-MRI and PW-MRI in the therapeutic timing of the brain stroke.

Imaging of stroke with DW-MRI:

A technique that is based on EPI (Echo planar imaging) imaging measures the random movement of the water molecules, their distribution in biological tissue during using the strong magnetic field gradients [7-9]. "Diffusion" is a term which used to describe molecular motion due to thermal random movements [precession][7]. This movement is being constrained by ligaments, membranes and macromolecules. Sometimes, the diffusion boundaries are oriented depending on the tissues structure. Diffusion of molecules also occurs on the both sides of the tissue, especially from bounded to free movement diffusion areas [7, 10]. This is called apparent diffusion coefficient (ADC). You can make a sequence sensitive to these movements by using two gradients on the both sides of the RF 180° pulse. It acts similar to the contrasted-phase MR angiography [MRA]. Hence, the static spins will have no pure phase changing after applying the gradients [8]. However, the dynamic spins will be affected by this phase change and will lead to a signal loss [6,7]. Since the normal tissue's moleculess can move unlimitedly, in "diffusion imaging" the normal tissue has lower signal intensity in comparison to an abnormal tissue. However, when pathology exists, the diffusion gets limited [7, 11]. The Brownian motion of molecules in extracellular fluid is more than intracellular matrix; since none of the intracellular membranous limitations, such as golgi system, endoplasmic reticulum which exist in the extracellular fluid. DWI is being performed by EPI sequences, due to it requires a high speed imaging method. One single echo in EPI can fill the entire K space [9, 12]. In DWI in sensitizing the sequences to the diffusion changes, the spin echo sequences have to utilize in order to apply the gradient on both sides of a RF 180° pulse. Usually an ultra-fast spin echo such as "SS_SE_EPI" is been used. It is not because of the fast speed in diffusion, but it uses to reduce other movements such as "flow", in a way that the "diffusion" is the only movement which measured [13, 14]. In order to capture the images in few seconds, almost the single or multi-shot SE-EPI is being used. However, the conventional spin echo can be used in fields with less motion artifacts [8-14]. There are two types of DW images:

1) Diffusion images or target images [trace]:

In DWI a damaged tissue, which has a limited diffusion and a lower ADC, appears brighter than a normal tissue, which has a free diffusion and a higher ADC or the lesions emerge as hyperintense regions on DWI and as correlative hypointense areas on apparent diffusion coefficient (ADC) maps, even after 3 minutes of stroke. The reason is the spins refocus in limited tissue [6, 9]. Since the spins remain in one place during the incitement and refocusing. However, diffusion is random in a normal tissue and the refocusing is not completed; therefore, the signal is omitted [Ref]. If the motion changes fast, weakening of diffusion befalls and the signal disappears in that area [7, 8, 10]. That is the reason that the abnormal tissue appears brighter than a normal tissue. Separated DWIs and applied gradients and (b value=1000) in these images are in a same direction with phase and frequency. The limited diffusion of water in acute cerebral infracted areas (i.e. cytotoxic edema) leads to a brighter DWI image comparing to the damaged areas [9, 10].

2) ADC map:

An ADC map is obtained by post-processing calculation of ADC for each single voxel and assigning the intensity according to its value. Therefore, the limited tissue which has a lower ADC is darker than a free diffusion area with a higher ADC. Thus, it is unlike the target images [9, 14]. When the luminosity in T2 [T2 shine through] becomes a problem, the ADC map could be useful. Shining in T2 shows damages or areas with a very long T2 time defect which remain bright in DW or target images. Therefore, it is difficult to know whether it is a representative of a region with limited diffusion or not [8, 12, 13]. It is possible to make a differentiation between areas with low ADC and an area with a long T2 time defect by creating ADC maps. ADC mapping make it possible to distinguish this area from other areas by having high signal intensity [6, 9]. These areas are representative of tissues with a long T2 time defect, but not for an area with a low ADC; in which each pixel represents the ADC of that location. ADC images appear dark for tissues in which the water movement is limited; thus, ADC is low in infracted tissues.

Sensitivity to diffusion is expressed by "b-value" with the unit of S/mm² [6, 9, 13]. The higher the b-value, the higher dephasing occurs; and the areas with limited diffusion produce higher signals. Diffusion gradients are applied symmetrically in three directions or more. These images can be combined in another image known as trace image that is an average of distinct geometric images. In clinical application, one obtains three images for each anatomical cut [6, 10]. DWI can detect the tissue damage within few minutes in complete blockage of blood vessels due to the quick onset of cytotoxic edema. The damaged tissue volume in DWI expands increasingly within 3 to 4 days which is a reflection of the adjacent infarction areas and also increasing the edema. As the cells die, their membrane gets destroyed and the biological barriers break down; thus, the damage volume begins to decline after the first week [8, 9, 10]. DWI can indicate the effects of a stroke only a few minutes after it happens. These effects display themselves as a signal decrease in ADC map that is indicative of an early stage cytotoxic edema. This leads to disorganization and depolarization in biological membrane and transaction of water around these membranes. SE-EPI with high b-value, about 1000 mm/s² is used in this method [8, 11]. The Advantage of EPI Imaging is its high-speed shooting within milliseconds, which could be useful in emergency clinical situations. DWI is useful to specify lacunar infarctions and atherosclerosis [9]. In addition, lesions on DWI indicate the ischemic core in which the cell concentration is more. The highest detection rate in DWI lesion is in the first 24 hours. ADC shows a sharp decline and it appears as a signal increase in DWI map after 24 hours. In all of the patients DWI is clearly determined 24 hours after the stroke. In some cases, such as atherosclerosis or lacunar ischemia it takes a little longer and the imaging can be time-consuming [9-12]. DWI is different depending on the amount, type, and the area that stroke occurs. In general, DWI can specify the potential lesion. Unlike the hyper acute stage, lesion on DWI depends on the area of the brain (or cerebral cortex) where the blockage occurs. It also depends on the blocked arteries, the degree of reduction in ADC, and the duration of stroke [9, 11, 14]. However, in many cases, abnormal signals in DWI represent damaged tissues by ischemia and the final infarction. The emission of ischemia with a high reduction in ADC contradicts the normal mode. DWI is potentially bigger and more accurate if the lesion in PWI is more than DWI and the onset of stroke is in the first 6 to 12 hours. In the first hours after a stroke, the ADC is reduced by about 30% or more than normal. ADC value of about 60×104mm²/sec is usually seen in ischemia. ADC value begins to increase again After 24 hours, it takes about 5 to 7 days for ADC to back to its normal level. Two of the pathologies in DWI that has a similar view to stroke include infections and cerebral abscesses, as well as epilepsy. Since DWI is very sensitive to changes in the neurophysiological changes in cerebral cortex, in epilepticus state one can see a hyper intensive DWI with a hyper perfusion. While in stroke there is a hypo perfusion which is along the valid measurements in ADC seen in acute cerebral infarction. Additionally, the following conditions increase the DWI signal: destruction of neurons and nervous fibers in multiple sclerosis, spinal cord injury, traumatic brain injury, and atherosclerosis of the intracranial artery due [15-18].

Artifacts of DWI methods:

Acute cerebral stroke is identified as a region with high signal, while other factors can increase signals. These are most important artifacts and origin of them that could confuse one when interprets the infarction by DWI methods [9-12, 19]:

· T2 Shine through artifact in which ADC map images and b-value of zero can be used for diagnosis, because the weight of diffusion images depends on the amount of spin density and being a T2W image [9,11].

· Hyper intensity artifact that may cause a Stroke view due to cerebral white matter diffusion anisotropy. DW is sensitive to diffusion, but only in one way. Routes with white matter leaflets that are laid diagonally in the same direction with applied diffusion gradients can be seen bright. This artifact is detected by experience and taking diffusion images in different dimensions. A way to remove this artifact completely is to check out the images that include isotropy weighting, images in which gradients are applied in every three directions. Such images are known as trace images [10,12].

· Another element that results in an artifact is hyper intense signals in DW scans which are related to susceptibility weighting. This artifact occurs on the border between bone-soft tissue, bone-air, and bone-foreign bodies like shunt. DWI-EPI sequence is sensitive to motion. Therefore, the patient should be completely quiet and motionless. It is very important that the patient's head be perfectly still. Scan time for such scans is less than 30 seconds. Parameters of this sequence depend on the applied equipment. Bolus of contrast agent for PWI imaging should be injected 10 seconds after the start of the EPI sequence. To specify a hemorrhagic stroke, adding spoil GRE with a minor Philip angle can be useful due an increase in sensitivity to susceptibility artifacts. To survey the internal carotid artery dissection, they add a SE T1W axial sequence which includes the upper part of the neck and skull base [10,12,20].

Imaging of stroke using perfusion weighted imaging [PWI]:

Clinical measurements of perfusion can be done by radiation detectors (radio tracers). Since MRI is a non-ionizing technique with high spatial and temporal resolution exhibiting detailed anatomical information; there is a great interest in perfusion MRI studies [11, 20]. Perfusion is a regional blood flow in tissue and defined as the blood volume that flows in one gram of tissue. Perfusion is a measurement of the quality of blood supply in a tissue. Since the blood supply and metabolism are usually associated, perfusion can be used to measure the activity of a tissue [Figure 1]. Perfusion can be done with two basic ways [11, 21]:

1-Arterial Spin Labeling: Hydrogen protons out of the head are marked and the flow of this endogenous contrast agent [marked spins] through the brain can be seen. This technique is not used in clinical applications since it needs a poor SNR and a long time.

2- The new method of using an external contrast: The composition is based on gadolinium (Gd) to act as a T2 contrast during the first pass through the cerebral vessels. The contrast agent causes a transient reduction in signal intensity (shortening effect of T2) proportional to the density in a certain area. This technique is known as acceptability dynamic contrast imaging (DSC). By using a fast imaging, typically EPI 50, consecutive images are achieved during the injection of contrast within about 70 seconds. Bolus contrast injection is done 5-10 seconds after the onset of imaging sequences to make sure that a sufficient number of base images can be obtained. Sufficient contrast dose is 0.2 mg/kg (mean for a person weighing 70 kg is about 30 ml). The injection rate is 5ml/s [catheter No. 18 in anterior cubital fossa] which is followed by 20-30 ml normal saline to remove the remaining gadolinium from the tube and the brachial vein and pulmonary artery [9, 11, 21]..

Although studies have shown that similar results can be achieved by monotone hand injecting. It is suggested that the imaging be done in 50 consecutive categories in 12 cutting status, so a set of 600 images can be obtained. If more cutting status is needed, it is necessary to select a longer TR and this will have a negative effect on the images quality. PWI is widely used in hyper acute and sub-acute stroke [11, 22]. However, while using a multi-detector CT (MDCT), CT-perfusion can be an option just as MR-perfusion. Many stroke diagnostic centers have started to use non-contrast CT for acute stroke diagnosis to rule out an intracranial hemorrhage [6]. Fallow shows ischemic areas by CT-perfusion, penumbra and CT-angiography display the zone of clot and blockage in the large arteries. Ischemic penumbra is like an area that functionally has been destroyed [6, 11]. A very important feature of this area is its ability to rebuild and seen and as an area with signal difference and mismatch (data mismatch between PWI and DWI, see below). If rCBV is constant but rCBF is slightly decreased, thrombolysis treatment will be done [11, 22]

Data mismatch between DWI and PWI:

In patients with acute stroke ischemic area extent characterized by PWI is usually more than a damaged parenchymal area characterized by DWI [9, 11]. In these patients, injection of an intravenous thrombolysis recombinant plasminogen activator r-[TPA] can be useful in 3 to 6 hours of onset of the stroke. PW and DW disharmony can be an indicative of the penumbra area. An abnormal DWI can be an indicative of an area of brain tissue where degeneration has occurred with cytotoxic edema and cell death. Penumbra area is an area where a decrease in CBF occurs but cell death is not happened yet [21-23]. However, without the use of specialized MRI techniques such as DWI and PWI, MRI is still more sensitive than non-contrast CT in detection of the acute stroke. The combination of DWI and FLAIR is a suitable sequence for imaging in hyper acute stages [11, 12] (see figure 2).

Penumbra is an area with a normal diffusion, but shows a decline in perfusion. A long transit time, for example a long time to peak and mean transit time, can be an important sign for mismatch data between diffusion and perfusion [11, 23]. However, the time defect of the TTP (Thrombotic thrombocytopenic purpura) leads to a Penumbra tissue overestimate. Because it is not only reflects the transit time, and also shows the circulation of collateral vessels. If MTT increases, it represents the transit time of the capillary bed in tissue of the intended area [21, 22]. Parson has proved that an increase or a decrease in MTT is a quantitative indicator about the possibility of increasing the risk of infarction [9, 21]. Applications that are used to determine the amount of MTT and its relation with infarct show various analyze. Some express the degree of MTT= 0 for infarct and some express the maximum amount of MTT. After the perfusion decreases, CBV will increase that is related to the dilatation of capillary bed. Area with reduced CBV and CBF represents the capillary bed area where the infarct has happened [22, 24].

Studies reported that in the infarcted tissue, rCBF in comparison by surviving tissue reduce about 10%. No specific threshold has been established to reveal the effectiveness of thrombolytic treatments for the PWI parameters. However, since no certain threshold has been stated to receive t-PA thrombolytic treatment, but studies show despite the vascular returning power which the tissue indicates by the normal rCBV and a small reduction in rCBF, the mismatch between DWI and PWI can be nominated for the thrombolytic treatment, yet, the reduction in rCBF and rCBV is a contra indication mode [11, 12, 25].

CONCLUSION:

Because the target of thrombolytic therapy in acute stroke is the brain tissue at risk of infarction, the most clinically relevant definition of the penumbra indicates the ischemic tissue but still viable and salvageable if local perfusion is efficiently restored. Elevated temperatures, or pyrexia, in the body or even in brain tissues are common in acute cerebral ischemic stroke. MRA can be performed in combination with brain MRI in the setting of stroke to help therapeutic decision making. It can detect high grade atherosclerotic lesions in the head and neck. It is also helpful for detecting less common causes of ischemic stroke such as carotid and vertebral artery dissection, and venous thrombosis. Traditional MRI remains a vital tool in the evaluation of the sub-acute stroke patients, due to its excellent soft tissue contrast. Specialized MRI techniques are essential to exclude hemorrhage in patient’s whom sub arachnoid hemorrhage (SAH) is suspected. MR with diffusion imaging can non-invasively detect ischemic changes and can be obtained within 10 minutes at some centers and dramatically alter care, so the clinical determination of ischemic stroke can be confirmed quickly. MRI with diffusion is quickly becoming the gold standard in acute stroke imaging but its use is limited because of the universal lack of access to this expensive equipment and technology, along with capable and experienced neuroradiologist to interpret the results. MRA is helpful for detecting less common cause of ischemic stroke such as carotid and vertebral artery dissection, and venous thrombosis. Angiography remains the gold standard against which all non-invasive assessments of carotid luminal narrowing and many types of cerebrovascular diseases which are identified and treated. Catheter angiography is an important tool in the hands of skilled interventionalist and continues to be the modality to which new therapies in stroke care are constantly evolving and being compared. While the ACR prefers MRI to CT for acute stroke, it is not currently available and practical for most centers.

ACKNOWLEDGEMENT:

Authors like to appreciate the Dr. Salehi and attendants for their helpful collaboration.

CONFLICT OF INTEREST:

No conflict of interest.

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Received on 28.05.2017 Modified on 21.06.2017

Research J. Pharm. and Tech. 2017; 10(6): 1951-1956.

DOI: 10.5958/0974-360X.2017.00342.0