Saturday, December 4, 2010

BASICS OF MR CONTRAST MEDIA

MRI CONTRAST MEDIA-MOLECULAR STRUCTURE AND RISKS ASSOCIATED WITH ITS USAGE IN PATIENTS.

INTRODUCTION Magnetic Resonance Imaging (MRI) is a technology used primarily in medical settings to produce high quality anatomical images of the human body in any plane without any change in the position of the patient. MRI is based on the principles of Nuclear Magnetic Resonance (NMR), a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules (Honark, 1996). The human body is mainly made up of fat and water, which consists of manly hydrogen atoms that make the human body approximately 63% of hydrogen atoms. MRI primarily images the magnetic resonance from the hydrogen nuclei (Hornak, 2007). The principle of nuclear magnetic resonance is based on the fact that, the nuclei of all elements have a magnetic moment and when these are exposed to stronger external magnetic field, these nuclei, especially of hydrogen atoms, tends to line up in an angular momentum (precession) according to the magnetic field. The frequency of precession (Larmor frequency-w0) is equal to the product of the strength of the magnetic field (b0) and a constant called gyro magnetic ratio (l). w0 = l b0 (Larmor Equation) The most important applications of Larmor Precession are MR spectroscopy and MRI. When the permanent magnetic dipoles of the nuclei are subjected to a very strong magnetic field, the spin of the nuclei precess around the magnetic field in either one of two directions, parallel or anti-parallel to the magnetic field. These two orientations are different in energy by . Where is the projection of the magnetic moment of the nucleus in the direction of the field. When external electromagnetic radiation (radio frequency-RF) is applied, the antiparallel nuclei can acquire a photon of energy exactly equal to the difference between the two states and change its state to the other direction (spin flipping). After some time it can relax to its old state and emit a photon of the same frequency, which constitutes the MR signal (McRobbie et al, 2003). Larmor frequency is very important in MRI to calculate the band width and the frequency of transmitting and receiving RF in order to reconstruct a particular MR image of the body part (Mackiewich, 1995). A Radio Frequency signal is applied through a transmitting coil to stimulate the lined up protons (in the nuclei). When the RF is turned off, the protons release energy and go back to the original position. The energy is absorbed and released in a particular manner determined by the chemical composition of the structure or the body part in which the atoms are located. The receiving coils collect the energy released by the protons and a sophisticated computer and display system is used to provide reconstructed images of the structures (Woodward, 2000).

Tissue contrast in MRI

MRI has the highest tissue contrast among all the imaging modalities used in modern medicine. Contrast is one of the major concerns in medical imaging that determines the ability to distinguish and characterize different structures with sharpness and accuracy from one another. All clinical diagnostic images must be able to demonstrate contrast between normal anatomical features and pathology. One of the main advantages of MRI compared with other imaging modalities is its excellent soft tissue contrast differentiation. A successful MRI study results in an image that exhibits sufficient contrast between areas of high signal and areas of low signal. High signal appears white, low signal appears dark and the intermediate signal intensities appear grey in the grey scale monitor. There are several factors that control or influence MRI contrast that is mainly divided into intrinsic and extrinsic factors. Intrinsic contrast factors are those that cannot be changed because they are inherent to the body tissues. Extrinsic factors are those that can be changed through adjustments in the MRI processes such as different pulse sequences, voxel size, number of acquisitions and the matrix size. However, there are many extrinsic factors in MRI contrast that can affect intrinsic factors and image quality. The signal intensity in MRI depends on the amount of water or hydrogen atoms present in the human body and the environment around that particular proton. Image contrast also depends on the magnetic relaxation times such as the T1 and T2 (MR tip, 2009). T1 is the spin lattice or longitudinal relaxation time which indicates the time required by the protons to regain longitudinal magnetization following an RF pulse. T1 is determined by thermal interactions between the resonating protons and other protons and other magnetic nuclei in the magnetic environment or "lattice". These interactions allow the protons to absorb the energy during resonance with RF and disperse to the surrounding medium once the RF is turned off. All molecules have natural motions due to vibration, rotation, and translation. Smaller molecules like water generally move more rapidly, thus they have higher natural frequencies. Larger molecules like proteins move slowly and if the water is held in hydration layers around a protein molecule, its rapid motion slows down considerably. T2 is spin-spin or the "transverse" relaxation time. It is a measure of how long transverse magnetization would last in a homogenous external magnetic field. T2 decay is due to magnetic interactions that occur between spinning protons. Unlike T1 interactions, T2 interactions do not involve a transfer of energy but only a change in phase, which leads to a loss of coherence. T2 relaxation depends on the presence of static internal fields in the substance. These are generally due to protons of larger molecules. These stationary or slowly fluctuating magnetic fields create local regions of increased or decreased magnetic fields, depending on whether the protons align with or against the main magnetic field. Local field non-uniformities cause the protons to precess (rotate) at slightly different frequencies. Thus following the 90 pulse, the protons lose coherence and transverse magnetization is lost. In T1 and T2 weighted pulse sequences, the echo time (TE) and repetition time (TR) are prescribed in such a away that T1 weighted image collect the signal from spin-lattice relaxation and T2 weighted image show the T2 decay (McRobbie et al, 2003). Despite the higher quality of MR images, it is essential to inject a contrast medium to investigate certain morphological and functional abnormalities of human body (Comblin et al, 1999). In addition to improving delineation between normal and abnormal tissues, the pattern of contrast enhancement can improve diagnostic specificity by facilitating characterization of the lesions in question. Contrast enhanced imaging can yield physiological and functional information such as dynamic contrast characteristics of pituitary gland, liver, breast and functional information such as perfusion imaging. Non-invasive Imaging of vascular system is another application of contrast imaging. When thinking of contrast media

in MR imaging, one must consider the fact that MRI works differently from CT scanning, which is also a modern imaging tool that requires contrast media administration for most of the cases. In CT scanning, the contrast media administered is radiation-absorbing material in order to delineate the structures. So the enhancement depends on the amount of contrast injected. It is hard to do this in MRI to increase the proton density to get more signals from a particular area (Volkov, 1997). The most effective way in changing appearance of different tissues on the MR image is achieved by changing the magnetic relaxation times of the protons in the tissue contained water. Therefore, contrast media in MRI is described as the chemical substances introduced into the body to increase or decrease the difference in signal intensity between normal and abnormal tissues by altering the relaxation time of that particular tissue (Woodward, 2000).

MRI CONTRAST MEDIA The Contrast media in MR are extrinsic compounds introduced into the body to alter the intrinsic contrast resolution of MR images. The MR contrast agents are classified into positive and negative contrast media according to the effective changes in the relaxation time after injection (MR tip, 2009). Positive contrast media produces increased signal intensity on T1 weighted images(the enhanced area appears more whiter than he surrounding tissue) and negative contrast media causes shorter T1 and T2 relaxation times in which T2 weighted effects are predominant and the enhanced region appears dark in T2 weighted scans. The T1 and T2 time constants dictate the shape of the exponential recovery and decay curves of the longitudinal and transverse magnetization, respectively. T1 is the spin-lattice or longitudinal relaxation time, and T2 is the spin-spin or transverse relaxation time. As mentioned above, MRI collects signal from the water protons, contrast agents enhances the relaxation of water protons in their vicinity. The common MR contrast media contains paramagnetic compounds with metal ions (e.g. manganese, iron and gadolinium), which possess large magnetic moments and are able to shorten the longitudinal and transverse relaxation time of protons (T1 and T2). Paramagnetic contrast agents (positive contrast agents) create magnetic fields approximately one thousand times stronger than those corresponding to water protons. These magnetic centers interact with water protons in exactly the same way as the neighboring protons, but with much stronger magnetic fields, thus reducing the relaxation rates, particularly on T1. The strongest, thus the commonest metal ion (among manganese, iron and gadolinium) used in current clinical imaging practice as MRI contrast, is gadolinium-based compounds (Bellin, 2006).

Molecular structure and Pharmacokinetics of Gadolinium based MR contrast media Gadolinium belongs to lanthanide group in periodic table and is classified as a metal whose atomic number is 64 and mass number is 157. Gadolinium alone is too toxic, if it is injected in its pure form because it will be deposited to bones and liver and produces liver necrosis. Binding to a chelate complex with gadolinium makes the ion chemically inert. Chelation is the formation of two or more separate bonds between a polydentate ligand and a single central atom (Gadolinium). Usually these ligands are bio-friendly organic compounds called chelants, chelators, chelating agents, or sequestering agents (Comblin et al, 1999). Therefore, MRI contrast agents are based on chelates of gadolinium (Runge, 2000). Gadolinium DTPA complex with a very high stability was the first contrast media approved by Food and Drug Administration of USA in mid 1988(Food and Drug Administration, 1988). The first

registered contrast medium is a gadolinium chelate, Gado- DiEthyleneTriaminePentaacetic Acid (Gd-DTPA). Chelate means "claw" and describes how the gadolinium ion (Gd3+) with three positive "unit charges" is trapped in a negatively charged chelate (cage) consisting of the dimeglumine salt of DTPA, which has 5 negatively charged carboxyl groups. The GdDTPA ion has 2 negative "charges" (+3 -5 =-2) and is accompanied by 2 positively charged meglumine ions for electro neutrality. The benefit gained by enclosing the Gd-ion in DTPA is that the Gd-DTPA ion has a ten times lower toxicity than the free or non-chelated Gd-ions. This DTPA detoxifying effect on the Gd-ion toxicity causes slight shielding of the magnetic field of the 7 unpaired electrons of the gadolinium ion with some decrease of its effects on the protons in the body.

DTPA are linear ion chelates. Another common chelate used in MR contrast media to bind the gadolinium ion is a cyclic molecule called gadolinium-Tetraazacyclododecanetetraacetic acid (Gd-DOTA) which is considered as more stable molecule (Bousquet et al, 1988).Most of the gadolinium complexes are derived from either DOTA or DTPA. According to molecular structures, the currently used MR contrast media are divided into groups such as cyclic chelates and linear chelates (Ide et al, 2006). The cyclic molecules offer better binding to gadolinium compared with the linear molecules (Dawson, 1999).

DTPA DOTA

Currently, seven gadolinium chelates are approved for clinical use in the international market. These paramagnetic agents can be classified into four main categories according to their biochemical structure, e.g., macro cyclic versus linear, and to their charge, ionic versus nonionic (Bellin et al, 2003). Macro cyclic, ionic contrast media shows more stability in holding the gadolinium in vivo.

The types, molecular structures and the brand names are given below in the diagram (Bellin et al, 2003).

The pharmacokinetic properties of Gd-DTPA are high water solubility, a small binding affinity for proteins and a low intracellular penetration (Almen and Aspelin, 2009). If the gadolinium ion is not chelated, it will be accumulated in the liver, spleen and the bones without being excreted. Chelated ions lead to rapid excretion though the kidneys. According to Bellin et al (2003) after chelation, the rate of renal excretion of the Gd complex is

increased approximately 550-fold compared with pre-chelation values. Gadolinium compounds are hydrophilic and they do not bind to proteins and other receptors. So the contrast medium injected is excreted unmetabolized in the urine. Gadolinium chelates are small molecules which can be diffused from the vascular space through capillaries into interstitial spaces. Most of the gadolinium compounds are extracellular fluid markers. They do not cross intact blood barriers such as in the brain and testes.

There are eight different kinds of gadolinium contrast media are available in United Kingdom. The brand name, molecular structure, chelate, charge and the elimination pathway are listed in the table below (Bellin, 2006).

Brand name Generic name Chemical structure Charge Elimination pathway Protein binding Omniscan gadodiamide Linear Non-ionic Kidney None OptiMARK* gadoversetamide Linear Non-ionic Kidney None Magnevist gadopentetic acid Linear Ionic Kidney None MultiHance Gadobenic acid Linear Ionic 97% Kidney, 3% Bile <5% Primovist gadoxetic acid Linear Ionic 50% Kidney, 50% Bile <15%

Vasovist Gadofosveset Linear Ionic 91% Kidney, 9% Bile >85% ProHance gadoteridol Cyclic Non-ionic Kidney None Gadovist gadobutrol Cyclic Non-ionic Kidney None Dotarem Gadoteric acid Cyclic Ionic Kidney None Mechanism of contrast enhancement The paramagnetic compounds used in MR contrast media have at least one unpaired electron. The electron has a magnetic moment approximately 1000 times greater than that of a proton simply because of its motion. By this virtue, MR contrast media causes rapid fluctuation of the local magnetic field at the atomic level. The effects of paramagnetic compounds can be compared to the function of enzymes i.e. enzymes increase the speed of reaction so that the equilibrium is reached more rapidly. Contrast media which shortens the relaxation times, works similarly to allow the magnetic moments of the hydrogen nuclei to return more quickly to their precession state, after they have been excited by the RF signal. Paramagnetic compounds can not prolong the relaxation times. Both T1 and T2 relaxation times are shortened after the administration of contrast media. Gadolinium ion has 7 unpaired electrons and it has the strongest effect on reducing T1 relaxation time (Felix et al, 1994). The ability of a particular MR contrast medium to reduce the relaxation time is called relaxivity. The sensitivity of the contrast medium increases with the relaxivity. Relaxivity can be measured experimentally at a constant magnetic field strength and temperature in specific medium such as water, plasma or cell culture. Paramagnetic MR contrast agent reduces both T1 and T2 relaxation times. When T1 is reduced, the signal intensity increases where as there will be a loss of signal intensity when the T2 is reduced in T1 and T2 weighted images (Woodward, 2000) Clinical applications of contrast media in MRI Almost 80% of the contrast injections in MRI are done in central nervous system diseases (brain and spine) and only 20-25% in the other parts of the body. With the modern high speed

MR scanners, it is now possible to study contrast enhancement patterns of different organs. Contrast enhancement is widely used in brain imaging for a variety of clinical conditions. Gadolinium has proven invaluable in imaging the central nervous system because of the ability of this agent to pass through disrupted blood-brain barrier. Most of the tumours in the brain can be demonstrated by contrast injection in MRI because of the disruption of blood brain barrier due to the presence of tumours. Dynamic perfusion studies of the brain have the capability of demonstrating the information about normal and pathophysiological brain function. Contrast enhanced MRI is extremely useful in characterising infections, multiple sclerosis, benign and malignant tumours of brain and spinal cord (Runge, 1996). Dynamic pituitary, breast and liver MRI scans are performed to detect and monitor different kind of tumours. Dynamic phase scanning with MRI contrast can provide a variety of diagnostic information about hepatocyte function, portal vein blood flow, and hepatic vein blood flow. Another recent advancement in MRI is the contrast enhanced angiography for almost all parts of the body (CE-MRA). Contrast enhanced dynamic scans of heart is another valuable tool for detecting myocardial viability in patients with myocardial infarction. Multi phasic liver scans after contrast injection is commonly used to diagnose haemangioma, hepatocelluar carcinoma and metastatic disease of liver (Dawson, 1999). The intravenous gadolinium-based contrast media is widely used in MRI of liver for a number of reasons: it improves sensitivity of lesion detection, and provides better diagnostic specificity and more accurate depiction of the extent of the disease involvement. Another application of MR contrast media is in MR arthrography where the gadolinium compound mixed with radiographic contrast media is injected into the joint space under fluoroscopy. Then the patient is brought to the MR scanner to examine the particular joint. MR arthrography gives excellent delineation of joint structures and pathology which is not visualized in the normal MR scan (Magee et al, 2004). Reactions to IV MR contrast Gadolinium-based agents are administered intravenously. The major route of excretion is through kidneys. Some of the newer contrast media compounds are excreted through urine and bile. Gadolinium agents tend to have a lower rate of adverse reactions than iodinated contrast agents. Risk factors include strong history of allergies, previous reaction to iodinated contrast, or previous reaction to gadolinium. At-risk patients can be premedicated with the same protocol used for iodinated contrast media such as hydration, antihistamines, and steroids. According to American College of Radiology (2008) mild reactions were selflimited events, exhibited no significant progression, and required no medical treatment (except administration of an antihistamine for cutaneous manifestations). Moderate reactions necessitated medical management (other than or in addition to antihistamine administration) or eventual outpatient transfer to the emergency department. Severe reactions were lifethreatening events (typically requiring hospital admission of an outpatient or emergency department patient). If a patient experienced more than a single contrast reaction manifestation, the reaction was categorized on the basis of the most medically significant sign or symptom. Adverse events to contrast material administration, such as nausea, vomiting, altered taste, perspiration, warmth, flushing, and anxiety, are considered as physiological side-effects. Such adverse events are not thought to be allergic-like in cause, do not typically require medical management. Most adverse effects are mild and self-limiting. Headache,

vasodilatation, and taste perversion have an occurrence of <10%; dizziness, nausea, and paresthesia may also occur infrequently. Allergic reactions to gadolinium agents are very rare (<0.1%). The enhancement of magnetism by gadolinium may cause sickle erythrocyte alignment, resulting in vaso-occlusive complications in the smaller blood vessels. Adverse reactions to intravascular contrast media vary from minor, self-limited physiological disturbances to major, life-threatening events and even death. The best means to treat a contrast media reaction is prevention, but when an adverse reaction occurs, the situation must be assessed rapidly, and appropriate treatment must be instituted as quickly as possible.. Therapy demands readiness to treat the full spectrum of potential reactions and requires the rapid availability of appropriately trained personnel, equipment, and medications anywhere intravascular contrast media are administered. It is very important that the practicing radiologists not only recognize and be able to treat complications specific to the radiologic procedure being undertaken, but also that he or she can recognize and treat other unexpected events (American College of Radiology, 2008).

The frequency of acute adverse reactions to gadolinium contrast media is about 8 times higher in patients with a previous reaction to gadolinium-based contrast media. Second time reactions to gadolinium-based media tend to be more severe than the first. Persons with asthma and various allergies are also at greater risk (American College of Radiology, 2008). According to Murphy et al(1996) adverse reactions to gadolinium contrast agents can be classified into four groups such as mild non-allergic reactions (nausea or vomiting), mild reactions resembling allergy (hives, diffuse erythema, or skin irritation), moderate reactions resembling allergy (respiratory symptoms), and life-threatening reactions resembling allergy (severe chest tightness, anaphylactic shock, respiratory distress, and penorbital edema). Minor discomfort of an extremity during injection, pain at the injection site, and coolness over the extremity on injection can occur in some cases. However these are not regarded as adverse reactions, as these sensations are common to many IV injections. Extravasations of MR contrast media around the injection site can cause skin redness, pain, swelling and even inflammation of the surrounding tissue and the vein. If the extravasated contrast media is ionic MR contrast, then the chances of inflammation is higher (Murphy et al, 1996). Gadolinium agents interfere with the laboratory test to determine calcium levels. The most common assay for serum calcium uses a colorimetric assay. Sometimes the effect is so exaggerated that the laboratory report shows serious hypocalcemia. This effect is common with higher doses; renal insufficiency increases the risk. Education of clinicians regarding this is essential to avoid the potential for incorrect diagnosis and initiation of inappropriate calcium replacement (Widmark, 2007). As a general rule, laboratory measurements on blood and urine should not be performed within 24 hours of administration of any contrast medium (Thomsen et al, 2007).

Risks associated with Gadolinium Contrast media The MR contrast media is extremely useful in diagnosing pathologies and malformations of the body structures. However, if the contrast media compound is dissociated inside the body and released free gadolinium ions, these Gd ions will interact with physiologic systems such

as the reticulo endothelial system, and can cause inhibition of the activity of some enzymes such as Ca2+-activated Mg-adenosine triphosphatase (ATPase) in the sarcoplasmic reticulum of skeletal muscle fibers, some dehydrogenases, kinases, glutathione S-transferases and aldolase via noncompetitive inhibition of Ca2+ binding. In vitro studies demonstrate that Gd3+ competitively inhibits Ca2+ ion binding to the transport sites on purified sarcoplasmic reticulum Ca-ATPase. The calcium channel inhibition effect of the free Gd3+ impacts on subsequent physiological processes that depend upon Calcium ions, such as neural transmission and blood coagulation. Gadolinium chloride inhibits phagocytosis in normal and activated Kupffer cells and decreases the total cytochrome content of hepatocytic microsomes. Free Gd ions forms complex with hydroxides and phosphates that are insoluble at a pH higher than 6.2. Phagocytosis of these complexes might depress the reticuloendothelial system, and might lead to foreign body reactions and fibrosis by inhibiting certain enzymes in the dermis (Bellin, 2006). In most of the patients, 50 % of the gadolinium compound injected for MR examination will be excreted in 2 hours time. In this short span of time, chances of dechelation or dissociation of the compound to release free gadolinium ions is very less with a stable contrast agent. If the contrast media is unstable or it is retained in the body for a prolonged period, free gadolinium is released from the chelated contrast media through a process called transmetallation. There are so many positive charged particles in our body system. Endogenous anions like Calcium (Ca), Zinc (Zn), Copper (Cu) and Iron (Fe) are able to destabilise the gadolinium complex and displace gadolinium from its ligand by competitive binding. During transmetallation, gadolinium ions are released into the system and the chelating complex with the new anions are excreted in urine. Urinary system is unable to eliminate pure gadolinium from the system and the dissociated gadolinium ions has poor solubility and could form precipitates of salts such as phosphate, carbonate and hydroxyl which will eventually deposited in liver, bone skin, muscle fibres and the interstitium (Deo et al, 2007). It has been reported in the literature that excretion of zinc and copper in urine is increased after intravenous injection of gadolinium based contrast media. This might be due to the transmetallation process of gadolinium compounds in vivo (Kimura et al, 2005).

In 1997, a new disease was first recognised as an idiopathic skin condition which causes skin thickening and hardening in the extremities and trunk, which is later identified as Nephrogenic Fibrosing Dermopathy (NFD) (LeBoit, 2003). Followed by another 15 cases of the same kind and surprisingly all the patients were on renal dialysis. Further studies showed that this condition not only affects the skin, but also associated with systemic involvement of other organs such as lungs, liver, muscles and the heart (Daram et al, 2005). This condition later named as Nephrogenic Systemic Fibrosis (NSF). Research undertaken on these initial cases showed that all patients with NSF had undergone MR examination with gadolinium based contrast media injection. Skin biopsies and tissue samples from NSF patients showed large amounts of gadolinium deposits. These findings led the researchers to conclude that gadolinium deposits in the body may have a greater role in the development of NSF (Boyd et al, 2007). Transmetallation occurs more quickly in acidic conditions. Thus it is obvious that in the clinical context of chronic kidney disease, where patients are frequently acidotic because they regularly receive bolus of intravenous iron products. The transmetallation process might be more rapid in patients with chronic kidney problems (Ide et al, 2006) Nephrogenic systemic fibrosis (NSF) is a rare scleroderma-like disease usually affects

patients with advanced renal insufficiency including those on dialysis. This condition was initially described as nephrogenic fibrosing dermopathy as skin involvement is a predominant feature. The skin lesions include large areas of hardened, scaly skin and raised lumpy plaques and nodes that affect upper and lower extremities, trunk and buttocks, but the face is usually not affected. Later it became apparent that the fibrotic changes may affect other organs such as liver, lungs, muscles and heart in addition to the skin, hence the terminology was modified to nephrogenic systemic fibrosis(Thomsen, 2006). The severity of the disease varies from one patient to another which may even cause serious physical disability including wheelchair requirement. The diagnosis of NSF is usually confirmed by deep skin biopsy to look for specific histopathologic features such as thickened collagen bundles with surrounding clefts, mucin deposition and a proliferation of fibroblasts and elastic fibres. Signs of inflammation are absent, which makes this disorder a different from other dermatological conditions (Swaminathan, 2008). The possible link between NSF and gadolinium was first reported in literature in 2006. In a study of nine patients who are undergoing regular dialysis had received MRI examination with gadolinium injection. After 2-4 weeks time, five of them developed skin thickening starting from lower extremities and spreading to the trunk and upper extremities. Histological examination revealed that all the five patients are affected with NFD (Grobner, 2006). Other causes which can trigger NSF along with gadolinium administration that are identified in the literature are metabolic acidosis, recent vascular surgery or vascular injuries, endothelial damage with elevated cytokines and angiotensin converting enzyme inhibitors(Cowper, 2003). In 2006, September another study comprising 13 patients with NSF was published and the study findings indicate that gadolinium plays a causative role in nephrogenic systemic fibrosis (Marckmann et al, 2006)

Considerations when selecting patient for contrast injection (Patient safety and dosages) Osmolality, ionicity, and viscosity need to be considered when reviewing MR agents. However, these factors are not as significant for the MR contrast agents as they are for other radiographic contrast agents because of the big difference in the amount injected. There is a common misconception that gadolinium-based agents do not cause contrastinduced nephrotoxicity. Reduced renal function is an important risk factor for contrast induced nephropathy. Gadolinium compounds are as nephrotoxic as iodinated contrast agents. Nevertheless, with the smaller volume administered (the standard dose is 0.1 mmol/kg, approximately 1020 ml)-the risk of contrast-induced nephropathy is so low that MR agents are considered virtually nonnephrotoxic. When higher doses (0.3 mmol/kg) are administered, the total osmotic load and the patient risk increase substantially. In a healthy adult patient, 98% of the gadolinium chelates injected intravenously will be eliminated in 24 hours through urine. If the contrast media remains in the body for a prolonged period, there is a chance of dechelation and release of free gadolinium into the system. Free gadolinium is highly toxic and this can be deposited in the bones and liver which in turn will cause necrosis (Thomsen et al, 2006). When selecting patient for MR contrast injection, a proper history and informed consent must be obtained. A screening form and check list must be used to screen all the patients prior to

the examination. The standard questions included are previous history of drug allergies, asthma, previous scan with contrast injections, vascular surgeries, renal insufficiency, sickle cell anaemia, clotting disorders, and dialysis in addition to the standard MRI safety questionnaire. The chances of adverse reactions to gadolinium-based contrast agents is about 2-3 times higher in patients with a history of reactions to iodinated contrast material. Patients with asthma and various allergies have a greater risk of adverse reactions (Nelson et al, 1995). The Royal Australian and New Zealand College of Radiologists (2007) recommend the following guidelines for administering gadolinium for MR examinations. The patient have to answer the following screening questions such as history of kidney disease as adult (including tumour, transplant, infection and trauma), family history of kidney failure (single kidney, CKD), age over 60 years with diabetes and/or hypertension, multiple myeloma, recent major surgery, Regular use of nephrotoxic antibiotics e.g. Aminoglycosides, hepatorenal syndrome and peri-operative liver transplant period. For outpatients with no history of allergic reactions and hypersensitivity to medications, the standard dose given is 0.1 mmol/kg (0.2 ml /kg which is usually capped at 10 ml of gadolinium contrast media). For inpatients and unwell outpatients eGFR must be obtained before proceeding with the injection of MR contrast media. For angiographic studies and breast dynamic studies, the volume of contrast media according to our department protocol is 20 ml of gadolinium contrast media. Patients with hypersensitivity or history of severe allergic reactions must be pre medicated with oral hydrocortisone for 3 days prior to the contrast enhanced MR examination (Murphy et al, 1996),(Dillman et al, 2008). Patients on peritoneal dialysis are contraindicated for enhanced MR Study. If enhanced MR is clinically indicated, the radiologist has to consult with the physician in charge of the patient and haemodialysis must be arranged immediately after the scan. Patients on regular heamodialysis must be injected with a more stable compound of MR contrast and these patients must undergo dialysis immediately after the scan. Over three dialysis sessions (9 hours), haemodialysis will clear gadolinium-based agents from the system. It is not recommended to administer gadolinium contrast media to infants below one year old because of their immature renal function (Thomsen et al, 2007).

Gadolinium chelates may accumulate in the amniotic fluid and remain there for an indefinite period of time, with potential dissociation of the toxic free gadolinium ion from the chelate; the significance of this exposure to the foetus is uncertain, and its potential association with NSF in the child or mother is unknown. A single cohort study of 26 women exposed to gadolinium chelates in the first trimester of pregnancy showed no evidence of teratogenesis or mutagenesis in their pregnancy. Currently, there is no evidence in literature to suggest teratogenicity of MR imaging with gadolinium on the fetus. However, the complete safety of the mother and foetus has not been proven yet. Therefore, recommendations regarding the use of gadolinium with a pregnant patient are largely based upon the risk-benefit principle (American College of Radiology, 2008). The plasma half-life of a Gd chelate is determined by the volume of distribution and the glomerular filtration rate (GFR) of that particular contrast medium. In healthy adults, the plasma elimination half-life for extracellular contrast agents following intravenous injection is approximately 7090 minutes. Most of the injected dose of the contrast agent is cleared from plasma via passive glomerular filtration within 24 hours in a person with normal renal function (Osakadal and Hals, 1993). If GFR for inpatients is more than 60 mL/min/1.73m,

the patients kidney function is assumed to be normal and a gadolinium contrast can be administered. The GFR is 30-60 ml/min, then the radiologist must be alerted and the need of an enhanced MR must be reviewed. If enhanced MR is clinically required, a more stable contrast media must be administered. For patients whose GFR is below 30 ml/min, gadolinium contrast media is contraindicated, unless there is an arrangement for haemodialysis immediately after the enhanced MR examination (Perazella, 2007).

Trends and Future developments Although MRI techniques with contrast injection can provide high quality images of the organs and tissues, the higher sensitivity required to visualize the biological targets of certain tissues is currently lacking. A contrast enhancement ability of 50 times beyond the current agents is required to achieve this goal. According to the theory of paramagnetic relaxation, the contrast enhancement can be further improved by slowing down the tumbling rate of the MRI contrast agent. Theoretically, this enhancement would be greater for contrast agents with an optimal rate of water exchange. The Hydroxypyridinone- Gd (GdHOPO)-based contrast agents have optimal water-exchange rates, whereas the commercial agents have slower non-optimal water-exchange rates; thus, the GdHOPO agents are ideal for attachment to macromolecules, which will slow down the tumbling rate of the contrast media molecules and increase the relaxivity. This strategy has been recently tested with the GdHOPO agents affording contrast enhancements 10-fold beyond the currently available commercial agents (Datta and Raymond, 2009). Hydroxypyridinone-based Gd complexes demonstrate more improved relaxivities due to their higher number of coordinated water molecules and better water exchange rates which is faster than that of currently available commercial agents. These complexes also have a higher thermodynamic stability which will be much safer for patients with renal insufficiency. Because of the higher relaxivity, the volume injected can be reduced further for a particular study (Raymond and Pierre, 2005). Super paramagnetic iron oxides are iron-containing compounds that shorten T2 and T1 relaxation times, with a predominant effect of decreasing T2 signal. They produce a longrange disturbance in magnetic field homogeneity in vivo. After intravenous injection of these iron oxides, there is a specific uptake of the contrast medium by the reticulo-endothelial system, mostly in the liver (80%) and in the spleen (5-10% of the injected dose) (Namkung et al, 2007). Some of the gadolinium based contrast media such as gadobenate dimeglumine (Primovist-Gd-BOPTA) and gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid (Multihance- Gd-EOB-DTPA) also can be used as tissue specific contrast media for liver imaging. The route of excretion of these contrast media is partially through the bile. So the contrast media injected will be concentrated in the liver shortly after injection (5-20 minutes) (Lupescu et al, 2008). Another area under research is lymph node specific contrast agents that contain ultrasmall superparamagnetic iron oxide particles (USPIO). But this contrast media are commercially available only in Europe at this time. MR imaging is performed 24 hours after IV administration of the agent. Normal or benign lymph nodes take up the USPIO agent, and malignant lymph nodes do not take up the USPIO. Lymph nodes that accumulate the contrast will appear dark on T2-weighted images (Harisinghani et al, 2003). Several orally administered MRI contrast agents have been developed for use in gastrointestinal imaging. Perflubron was the first commercially available oral MRI contrast agent that produces a

signal reduction within the bowel lumen on T1- and T2-weighted images, therefore acting as a negative contrast agent for abdominal MR studies. Ferumoxsil is the only oral MRI contrast agent currently available in the United States and it contains iron particles that acts as a negative contrast media for bowel studies (Gastromark, 2009).

Radiographers roles and responsibilities in MR contrast administration Our department policy is that all paediatric and adult patients having allergic-like reactions to contrast media, whether gadolinium- or iodine-containing, must be evaluated in person by a radiologist. It is the MR radiographers sole responsibility to observe patient closely for any acute reactions or changes in the vital signs of the patient during the scan and immediately after the scan. Communication with the patient is very important in all the cases. In case of any reaction, the radiologist in-charge must be alerted to assess the patient. After patient assessment and management of the contrast reaction, the treating physician is required to document the details of the event by completing a standardized departmental contrast material reaction form. The radiologist reporting the particular MR examination is supposed to document the adverse reaction onto the radiology report as well. This will aid the radiographers to trace any history of the patient through radiology information system in future. Patient is to be administered MR contrast agents only after receiving written orders from a duly licensed physician or radiologist. Intravenous injection-qualified MR radiographer or nurse can set a peripheral IV access line, if they have undergone the requisite site-specified training in peripheral IV access and have demonstrated and documented appropriate proficiency in this area. We are in line with the policy of Dr.Kanal that IV-qualified MR radiographers may administer gadolinium-based MR contrast agents via peripheral IV routes as a bolus or as a slow or continuous injection as directed by the orders of a duly licensed site physician (Kanal et al, 2007). The MR radiographers responsibility in the MR suite is not limited to the safety of patient from the strong magnetic field. If the clinical indication warrants an enhanced MR examination, the patient must be screened and an informed consent for contrast injection must be obtained before the patient is positioned in the magnet. This practice will speed up the work flow and reduce the time between the pre and post contrast scans, thus reducing movements and repositioning time. A proper history of the patient including previous adverse reactions, MR scans with contrast injections, renal functions, history of dialysis must be obtained prior to any contrast media injections. Recent GFR must be documented on the request form wherever applicable. A proper inventory and usage of contrast media must be kept for auditing purposes. The expiry date must be verified personally before the administration of contrast media. The colour and state of the contrast material must be visually inspected before the radiographer drawing the contrast media into the syringe. All the radiographers trained for IV cannullation and IV injection must be also trained for aseptic technique for contrast media administrations. Do not contaminate the solution, needles and catheters for injection. This applies to the loading of automatic injectors and priming of connection tubing. Proper documentation of the dose, type and lot number of the particular contrast media is very important in case the patient developed any adverse reactions from the injection. When administering gadolinium

contrast media do not exceed the recommended dose and discard any unused portion of contrast media in the syringe. Once exposed to atmosphere, the chance of crystallisation and growth of microorganisms is high for the gadolinium based contrast agents. The radiographer in-charge in MR suite should discuss with the radiologist and manager and determine the size and volume which is optimal for the departments work flow to reduce wastage and contamination of the contrast media in the vials. MR contrast media are available in several types and sizes such as preloaded syringes for manual and auto injections. If vials are to be used for multiple patients, strict aseptic practice must be used when drawing the contrast. The rubber septum of the vial should be wiped with an antiseptic alcohol swab and a new needle and syringe should be used each time a vial of contrast media is punctured. All opened vials should be labeled with a date and time and stored in a clean, dry place at room temperature away from bight light (Green et al, 1995). In our radiology department, there is a radiologist who is in charge of MR suite, who is supervising the work flow and reviewing the department protocols from time to time in order to keep the department up-to-date with the ever-growing technology. As a principal radiographer and modality leader in MRI, my responsibilities include teaching and training of new staff in the MR area. Not only in the MR safety, but also to arrange the frequent CME sessions to share up to date information, MR protocols and work arrangements etc. It is my duty as a leader to pass the knowledge on to the juniors which I gained from my experience all these years, especially in identifying signs of early contrast reactions with vigilance and communication with the patient during the MR examination. Every three months we conduct a trial run for emergency situations such as code blue (Code which is used to activate the emergency medical team when a patient collapse) to evaluate the preparedness of our team in radiology. It is my duty together with the radiology nurse to make sure all the facilities such as the emergency cart and resuscitation drugs are readily available in any unforeseen incidents. In addition, I make sure all my radiographer are trained, certified and competent in IV canulation and Cardio pulmonary resuscitation techniques(BCLS-Basic Cardiac Life Support.)

Conclusion and reflection Over the past decade, gadolinium based MRI contrast media has been in clinical use for variety of conditions. The gadolinium chelates are the dominant class among all the agents. These agents aid in improving the diagnostic accuracy by indirectly affecting the contrast of pathological processes. Lesion enhancement occurs either by disruption of blood brain barrier or lesion vascularity. Therefore, the contrast enhancement is used mainly for both improved detection of lesions and characterization. Originally developed for neurological applications, new types of contrast agents have been developed with improved relaxivity and altered distribution for other organs such as liver and vascular applications. Although relatively safe, free gadolinium ions can pose serious health risks in individuals with impaired renal functions. Even though a small percentage of death reported, NSF is a severe disabling disease with complications associated with accumulation of free gadolinium in heart, blood vessels and skin of the affected patients. In view of these recent developments, utmost care should be taken in screening and selecting the patients prior to administering these agents. MRI radiographers have a vital role in ensuring the safe administration of contrast agents. It is of utmost importance that the radiographers in MRI understand the effect of gadolinium based contrast agents on patients with compromised renal function and those at high risk. A

proper screening involving clinical history and risk factors must be included for all enhanced examinations. A written policy pertaining to the proper administration of all contrast media agents should be in place in every MRI suite. Radiographers and Radiologists and physicians should work hand in hand in a collaborative effort to make sure the benefits outweigh the risks in patients requiring contrast agents for MRI examinations. Most contrast agents available for clinical use today require significant amount (gram quantities) of gadolinium in order to produce adequate enhancement and changes in contrast in the final image. Moreover, these are agents are limited to target certain sites where they accumulate in high concentration mainly in the blood stream. Newer agents are however targeted site specific with much higher relaxivities needed to account for the reduced concentration for increased tissue specificity (Raymond and Pierre, 2005). The future of MRI contrast agents might probably be with HOPO family of Gd III chelates. Studies with this family reveal promising findings. Unlike the agents we have today, these agents possess remarkable and a unique combination of high hydration numbers, fast water exchange rates, astounding stabilities and tremendously high relaxivity values particularly at the region of interest (Werner, 2008). As the number of MRI examinations performed with contrast agents increase at alarming rate, the quest for a safe, stable, tissue and site specific agents will continue to evolve in the coming years. The new contrast agents will certainly pave the way for a paradigm shift in the diagnosis of many pathological conditions. It is an exciting world for the researchers and manufacturers. The ultimate beneficiaries are undoubtedly our patients but it is our responsibility as MRI professionals to ensure their safety is of paramount importance. References Almen, T. and Aspelin, P. (2009) Medicylopaedia [Online] Available from: http://www.medcyclopaedia.com/library/radiology/chapter07/7_5.aspx?s=mr+contrast+medi a&mode=1&syn=&scope= [Accessed 25 October 2009) AMAG Pharmaceuticals (2009) GastroMARK [Online] Available from: http://www.amagpharma.com/products/gastromark.php [Accessed 22 Nov 2009] American College of Radiology. (2008) Manual on contrast media, Version 6.[online] Available from: http://www.acr.org/contrast-manual. [Accessed on25 october 2009] Bellin, M. (2006) MR Contrast agents, old and new, European Journal of Radiology, 60 (3), pp. 314-323. Bellin, M. F., Vesile, M. and Morel-Precetti, S. (2003) Currently used non-specific extracellular MR contrast media, European Journal of Radiology, 13 (12), pp. 2688-2698. Bousquet, J. C., Saini, S., Stark, D. D., Hann, P. F., Nigam, M., Wittenberg, J. and Ferrucci, J. T. (1998) Gd-DOTA: Characterization of a new paramagnetic complex, Journal of Radiology, 166 93), pp. 693-98. Boyd, A. S., Zic, J. A. and Abraham, J. L. (2007) Gadolinium deposition in nephrogenic fibrosing dermopathy, Journal of American Academic Dermatology, 56 (1), pp. 2730. Comblin, V., Gilsoul, D., Hermann, M., Humblet, V., Jacques, V., Mesbahi, M. and Sauvage, C. (1999) Designing MR contrast agents: a coordination chemistry challenge, Coordination Chemistry Reviews, 185, pp. 451-475.

Cowper, S. E. (2003) Nephrogenic Fibrosing Dermopathy: the first six years, Current Opinion in Rheumatology, 15(6), pp. 785-790. Daram, S. R., Cortese, C. M. and Bastani, B. (2005) Nephrogenic Fibrosing Dermopathy/Nephrogenic Systemic Fibrosis: Report of a New Case With Literature Review, American Journal of Kidney Diseases, 46 (4), pp. 754-59. Datta, A. and Raymond, K. N. (2009) Gd-Hydroxypyridinone(HOPO)-based high relaxivity magnetic resonance imaging(MRI) contrast agents, Accounts of Chemical Research, 42 (7), pp. 938-947. Dawson, P., Cosgrove, D. O. and Grainger, R. G. (1999) Textbook of Contrast Media. Oxford: Isis Medical Media. Dawson, P., Cosgrove, D. O. and Grainger, R. G. (1999) Textbook of contrast media. London: Informa Health care. Deo, A., Fogel, M. and Cowper, S. E. (2007) Nephrogenic Systemic Fibrosis: A population study examining the relationship of disease development and gadolinium exposure, Clinical Journal of American Society of Nephrology, 2 (2), pp. 264-267. Dillman, J. R., Ellis, J. H., Cohan, R. H., Strouse, P. J. and Jan, S. C. (2008) Allergic-Like Breakthrough Reactions to Gadolinium Contrast Agents After Corticosteroid and Antihistamine Premedication, American Journal of Roentgenology, 190, pp 187-190. Felix, R., Heshiki, A., Hosten, N. and Hricak, H. (1994) Magnivist monograph. London: Blackwell publications. pp 5-8. Green, K. A., Mustachi, B., Schoer, K., Moro, D., Blend, R. and McGeer, A. (1995) Gadolinium-Based MR Contrast Media: Potential for Growth of Microbial Contaminants When Single Vials Are Used for Multiple Patients, American Journal of Roentgenology, 165 (3), pp. 669-671. Grobner, T. (2006) Gadolinium- a special trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis, Journal of Nephrology Dialysis Transplantation, 21(4), pp. 1104-1108. Harisinghani, M.G., Barentsz, J. and Hahn, P. F. (2003) Non-invasive detection of clinically occult lymph-node metastases in prostate cancer, The New England Journal of Medicine, 348 (25), pp. 2491-2499. Hornak, J. P. (2007) The Basic of MRI [Online] Available from: http://www.cis.rit.edu/htbooks/mri/index.html [Accessed 12 September 2009] Ide, J., Port, M., Raynal, I., Schaefer, M., Greneur, S. L. and Corot, C., (2006) Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review, Fundamentals of Clinical Pharmacology, 20 (6), pp. 56376.

Kanal, E., Barkovich, A. J., Bell, C., Borgstede, J. P., Bradley, W. G., Froelich, J. W., Gilk, T., Gimbel, J. R., Gosbee, J. and Sass, N. (2007) ACR Guidance Document for Safe MR Practices, American Journal of Roentgenology, 188 (6), pp. 1-27.

Kimura, J., Ishiguchi, T., Matsuda, J., Ohno, R., Nakamura, a., Ohno, K., Kawamura, T. and Murata, K. (2005) Human comparative study of zinc and copper excretion via urine after administration of magnetic resonance imaging contrast agents, Journal of Radiation Medicine, 23 (5), PP. 322-326.

Klasson, A. (2008) MRI Contrast Enhancement using Gd2O3 Nanoparticles [Online] Available from: www.ep.liu.se/smash/get/diva2:17500/FULLTEXT01 [Accessed 11 November 2009]

LeBoit, P.E. (2003) What nephrogenic fibrosing dermopathy might be, Arch Dermatol, 139(7), pp. 928-930. Lupescu, I. G., Capsa, R. A., Gheoghe, L., Herlea, V. and Georgesu, A. (2008) Tissue Specific MR Contrast Media Role in the Differential Diagnosis of Cirrhotic Liver Nodules, Journal of Gastrointestinal and Liver diseases, 17(3), pp. 341-346. Lupescu, I. G., Capsa, R. A., Gheorghe, L., Herlea, V. and Georgescu, S. A. (2007) Tissue Specific MR Contrast Media Role in the Differential Diagnosis of Cirrhotic Liver Nodules, Clinical Imaging, 17(3), pp. 341-346. Mackiewich, B. (1995) Basic principles of MR Imaging [Online] Available from: http://www.cs.sfu.ca/~stella/papers/blairthesis/main/node10.html [Accessed 10 October 2009] Magee, T., Williams, D. and Mani, N. (2004) Shoulder MR Arthrography: Which patient groups benefit best, American Journal of Roentgenology, 183 (4), pp. 969-974. Marchmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, M. B., Heaf, J. G. and Thomsen, S. K. (2006) Neprogenic Systemic Fibrosis: Suspected Cauasative Role of Gadodiamide Used for Contrast Enhanced Magnetic Resonance Imaging, Journal of the American Society of Neprology, 17 (9), pp. 2359-2362. Markisz, J. A., and Whalen, J. P. (1998) Principles of MRI. 2nd ed. Michigan: Appleton and Lange. McRobbie, D.W., Moore, E. A., Graves, M. J., and Prince, M. R. (2003) MRI from Picture to Proton. 2nd ed. London: Cambridge University Press. MR-TIP (2009) Chemical Shift. [Online] Available from: http://www.mrtip.com/serv1.php?type=db1&dbs=Chemical%20Shift [Accessed 23 Dec 2008] MR-TIP (2009) Contrast agents [Online] Available from: http://www.mr-

tip.com/serv1.php?type=db1&dbs=Contrast%20Agents [Accessed 23 October 2009] Murphy, K. J., Brunberg, J. A. and Cohan, R. H. (1996) Adverse reactions to gadolinium contrast media: a review of 36 cases, American Journal Radiology, 167 (4), pp. 847-849. Namkung, S., Zech, C. J., Helmberger, T., Reiser, M. F. and Schoenberg, S. O. (2007) Superparamagnetic iron oxide (SPIO)-enhanced liver MRI with ferucarbotran: efficacy for characterization of focal liver lesions, Journal of Magnetic Resonance Imaging, 25 (4), pp. 755-765. Nelson, K. L., Gifford, L. M., Lauber-Huber, C., Gross, C. A. and Lasser, T. A. (1995) Clinical safety of gadopentetate dimeglumine, Clinical Radiology, 196 (2), pp. 43943. Oksendal, A. and Hals, P. (1993) Biodistribution and toxicity of MR imaging contrast media, Journal of Magnetic Resonance Imaging, 3 (1), pp. 157165. Perazella, M. A. (2007) Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link, Clinical Journal of American Society of Nephrology, 2 (2), pp. 200-202. Raymond, K. N. and Pierre, V. C. (2005) Next Generation, High Relaxivity Gadolinium MRI Agents, Journal of Bioconjugate Chemistry, 16 (1), pp. 3-8. Runge, V. M. (1996) Contrast enhanced clinical magnetic resonance imaging. Kentucky: University press of Kentucky. Runge, V. M. (2000) Safety of approved MR contrast media for intravenous injection, Journal of Magnetic Resonance Imaging, 12 (2), pp. 20513. Siegle, R. L. Halvorson, R. A.and Dillion, J (2007) Manual on Contrast media version 5.0 [Online] Available from: http://radipedia.com/WikiMedia/images/e/e0/ACR_Contrast.pdf [Accessed on 21 nov 2009] Swaminathan, S., High, W. A. and Ranville, J. (2008) Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis. Kidney International, 73, pp.1413-1418. Thomsen, H. S. (2006) Is there a casual relation between the administration of gadolinium based contrast media and the development of neprogenic systemic fibrosis (NSF), Journal of Clinical Radiology, 61 (11), pp. 905-906. Thomsen, H. S. (2006) Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide, European Radiology, 16 (12), pp. 26192621. Thomsen, H. S., Marckmann, P. and Logager, V. B. (2007) Nephrogenic Systemic Fibrosis (NSF): a late adverse reaction to some of the gadolinium based contrast agents, Cancer Imaging, 7(1), pp. 130-137. Thomsen, H. S., Morcos, S. K. and Dawson, P. (2006) Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF), Clinical Radiology, 61(11), pp. 90506.

Volkov, A. (1997) Contrast agents in Magnetic Resonance Imaging [Online] Available from: http://home.utah.edu/~av6a51/mri.htm [Accessed 20 October 2009] Werner, E. J. (2008) High-Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging [Online] Lawrence Berkeley National Laboratory: Lawrence Berkeley National Laboratory. Available from: http://escholarship.org/uc/item/68h1s8g8 [Accessed 10 Nov 2009] Westbrook, C., Roth, C. K. and Talbot, J. (1998) MRI in practice. 2nd ed. London: Blackwell Publishing. Widmark, J. M. (2007) Imaging-related medications: a class overview, Baylor University Medical Center Proceedings, 20(4), pp. 408-417. Woodward, P. (2000) MRI for technologists. 2nd ed. New York: McGraw-Hill.

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Lindon, J.C. (2007) The hand bood of metabonomics, London: Elsevier. Rinck, P.A. (2001) Magnetic Resonance in Medicine: The Basic Textbook of the European Magnetic Resonance Forum. 4th ed. NJ: Blackwell Science. Westbrook, C., Kaut. C. and Talbot, J. (2005) MRI in Practice. 3rd ed. NJ: Blackwell Science. Posted by SANTHOSH at 4:29 AM 0 comments

MR Spectroscopy (MRS)

MAGNETINC RESONANCE SPECTROSCOPY (MRS)

Introduction Magnetic Resonance Imaging or MRI represents a breakthrough in medical diagnostics and research in this century. Its development was one of several powerful imaging techniques that revolutionized medicine by allowing physicians to explore bodily structures and functions. Over the past two decades, advances in the computer technologies coupled with unprecedented growth in the hardware sophistication paved the way for MRI to be most powerful diagnostic tool in modern medicine. In addition to providing exquisite detail of anatomical structures, MRI has evolved to be capable of measuring different metabolite levels in body tissues, the area now known as MR spectroscopy or MRS. In this essay; an attempt is made to understand the underlying principles of MRS and its clinical relevance in diagnostic radiology today.

Magnetic Resonance Imaging (MRI) Magnetic resonance imaging is a technology used primarily in medical settings to produce high quality anatomical images of the human body in any plane without repositioning the patient. MRI is based on the principles of nuclear magnetic resonance (NMR), a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules. The human body is mainly made up of fat and water, which consists of many hydrogen atoms, that makes the human body approximately 63% hydrogen atoms. MRI primarily images the magnetic resonance from the hydrogen nuclei (Hornak, 2007). The principle of nuclear magnetic resonance is based on the fact that, the nuclei of the elements have a magnetic moment and when these are exposed to stronger external magnetic field, these nuclei tends to line up in an angular momentum (precession) with the field. The frequency (Larmor frequency-w0) is equal to the product of the strength of the magnetic field (b0) and a constant called gyro magnetic ratio (l). w0 = l b0 A radio frequency (RF) is then applied to stimulate these lined up protons (in the nuclei) with the use of a transmitting coil. When the RF is turned off, the protons release energy and go back to the original position. The energy is absorbed and released in a fashion determined by the chemical composition of the particular structure in which the atoms are located. The receiving coils collect the energy released by the protons and a sophisticated computer and display system is used to provide reconstructed images of the structures (Woodward, 2000).

Magnetic Resonance Spectroscopy (MRS)

Nuclear magnetic resonance spectroscopy commonly known as Magnetic Resonance Spectroscopy (MRS) is a technology that exploits the magnetic properties of certain nuclei. MRS allows the doctors to obtain biochemical information about the molecules inside the human body without doing a biopsy. So it is also called as in-vivo MRS. In MRI the signals are used to reconstruct an image of the organs whereas in MRS the signals gives a spectrum that contains information about the chemical composition of metabolites in the body. The common nuclei used in MRS are hydrogen (Equals to proton), sodium (Na) and phosphorus (P) and carbon(C). Since hydrogen is abundant in the body tissues, it is easier to perform proton spectroscopy and provides higher signal to noise ratio. The spectroscopy using signals from hydrogen or proton is called proton spectroscopy. Proton spectroscopy can be performed using the same coil that uses for MRI and can be conveniently added on to the routine MRI protocols. The resultant spectra can be used to monitor biochemical changes in tumours, infections, stroke, epilepsy, metabolic disorders and neurodegenerative diseases (Hesselink, no date). Basic physical principles and techniques The resonant frequencies of nuclei, when it is exposed to an external magnetic field, are at the lower end of the electromagnetic spectrum between radio waves and radar waves. The resonant frequencies of protons range between 10 MHz in 0.3 tesla (T) magnetic field and about 300 MHZ on a 7T magnet. This means higher the field strength gives a better signal to noise ratio and better separation between the peaks of different metabolites. The hydrogen atom (proton) exhibits different resonant frequencies in different chemical composition because of the chemical bonding is in various metabolites. The nuclei or protons with different chemical environment show slightly different resonance frequencies given by the equation: w0 = l b0 (1-s) Where s is a screening constant represents the small change in resonance frequency in different molecules which is known as chemical shift. Chemical shift is the basis of MR spectroscopy. s is decided by the molecular structure and the position of proton within the molecule(Honark,2007). The resonance frequencies of the protons are not only affected by the electron clouds surrounded by it, but also due to the interaction between the spins of neighbouring protons, which is known as scalar coupling or spin-spin splitting or J coupling. J coupling can produce splitting of spectral lines into slightly different frequencies for the same proton in a particular metabolite (MR-TIP, 2009 a) The basis of signal production is MRS is similar to MR imaging. Once the patient is placed in the bore of magnet, all the protons will be aligned according to the magnetic field either parallel or anti-parallel direction according to the larmour frequency. Shimming is done to make the magnetic field uniform and a radio frequency pulse is applied, usually a 90 degree pulse, which rotates the protons from z-axis to the x-axis. When the Rf pulse is turned off, the nuclei returns to its original position. The time taken by the nuclei to return to the original position is according to their relaxation times. The receiving coils placed closer to the body part will detect the energy released by the protons and the voltage variation is called free induction decay. This free induction decay is plotted as an exponential decay function and using fourier transformation, a plot of frequency domain is obtained which shows different larmour frequency at different peaks. The peaks occur at different time intervals for different metabolites. Each peak on the plot or spectral graph depends on the chemical environment of that particular nucleus and usually expressed in Hertz (Hz)(Castillo et al, 1996). In 1.5 tesla MR scanner, the proton spectra of observable metabolites are spread out between

63 to 64 MHz (63-64 million Hz). In order to make the graph more simple, the resonant frequencies are expressed in parts per million (ppm) and the ppm scale reads from right to left (See appendix for the observable proton metabolites in human body). For normal MRI of human body, the signals mainly come from fat and water. If the same signal is used for MRS, the fat and water peaks in the spectrum will be huge and scaling will make it difficult to visualise the signals from the metabolites. So in MRS, we are not interested in the signals from fat and water. Signal from fat is avoided by fat suppression techniques and water suppression is achieved by inversion recovery (IR) or chemical shift selective technique (CHESS). These suppression techniques are used in pulse sequences for obtaining signals from metabolites from the selected part of the body. Pulse sequence is defined as preselected set of defined RF and gradient pulses, usually repeated many times during a scan, wherein the time interval between pulses and the amplitude and shape of the gradient waveforms will control NMR signal reception and affect the characteristics of the MR images. Pulse sequences are computer programs that control all hardware aspects of the MRI measurement process(MR tip, 2009 b). Inhomogeneity in the magnetic field also can affect the spectrum obtained. In order to improve the magnetic homogeneity, shimming must be performed before the spectro scan. Shimming is a process to improve the homogeneity of the magnet by adjusting the direct current (DC) in the gradient coils and the shim coils in the magnet. A homogenous field can improve the sensitivity and resolution of the spectrum (Miner and Conover, 2003). One of the common techniques used in MRS is Single Voxel Spectroscopy (SVS) . In this technique, the main pulse sequences used are spin echo (SE) or point resolved spectroscopy (PRESS) and stimulated echo acquisition method (STEAM). Steam has been widely used in spectroscopy because the content of information regarding the metabolites can be altered according to clinical condition by selecting an appropriate echo time for the sequence (TE)(Chary and Govil, 2008). Another acquisition method used is multivoxel spectroscopy or Chemical Chift Imaging (CSI) (Hesselink, no date). Chemical shift imaging allows metabolite information to be measured in an extended region and to add the chemical analysis of body tissues to the potential clinical utility of MRS. The spatial location is phase encoded and a spectrum is recorded at each phase encoding step to allow the spectra acquisition in a number of volumes covering the whole sample. CSI is useful in mapping of chemical shifts, analogue to individual or more than one spectral lines. The resolutions can be in more than one direction. But the acquisition time for multivoxal spectroscopy is quite long and if the patient moves during the scan, the information obtained may not be ideal for diagnosis. In MRS, the echo time (TE) affects the information obtained. If the TE is short (e.g. 30ms), metabolites with short and long T2 relaxation times can be plotted. With a long TE of 270 ms (millisecond), only those with long T2 relaxation time can be seen. So the radiographer who is doing the scan must be aware of the clinical condition, the metabolites in question and their corresponding relaxation times. A strong and very homogenous magnet is needed to differentiate the resonance peaks of the metabolites. The resolution and separation in between the metabolites gets better with the strength of the magnet. Specific pulse sequences must be available for signal acquisition together with adapted data processing software (Hoa, 2007). The signal processing comprises of several processing steps such as zero-filling or adaptation filtering to complete the digital signal, phase correction to obtain the actual part of the spectrum and there must be a base line correction available (McRobbie et al, 2007). Poor water suppression or fat suppression will affect the spectral resolution adversely. Saturation bands bands must be placed in all direction to make sure the signals come only from the region of interest. Communication with the

patient and patient co-operation is crucial in spectrooscopy scans. Clinical applications In the era of stronger and faster MRI machines, MRS provides a tool to monitor the cellular energy utilization as well as providing other indicators of functional behaviour. MRS can be performed together with the diagnostic MR imaging, so that there is an intrinsic spatial registration between the spectrum and the anatomy. Main clinical applications of MRS can be divided into two categories such as clinical research and clinical routine. Clinical research deals with a group of subjects for a certain reason (for future developments and testing of protocols, coils, software etc). Clinical routine is used in decision making for an individual patient. Proton spectroscopy is widely used in clinical practice today for identifying and diagnosing functional abnormalities and tumours. It also can be used as a tool to pinpoint the location for biopsy and surgical excision of a tumour (Kries, 2000).

Brain The clinical importance of brain MRS depends on the nature and concentration of brain chemicals and the spectrum is analysed in comparison with the MR images. If there is a particular neuro-chemical shows high peaks, the graph must be compared with that of normal brain tissues also. This is a spectral graph of normal brain (Sergio et al, 2003). The metabolites, which can be identified by MRS of brain, are as follows (Gillard et al, 2005). NAA (N-Acetyl Aspartate), ppm 2, a neuronal marker Cr (Creatine), ppm 3&3.9, a marker for energy conversion (ADP-ATP) usually appears in two peaks. Cho (Choline), ppm 3.2, Increased Cho indicated increased membrane synthesis/increased number of cells. Ml (Myo-inositol), ppm 3.6, marker of hormone- inositol diphosphate. Glu & Gln (Glutamate and glutamine- Glx), ppm 2.1-2.5, Neuro transmitter and regulator. Lip (Lipids), ppm 0.9-1.4, an indicator of cell breakdown. Lac (Lactate), ppm 1.3, end product of anaerobic glycolysis. Increased Cho and decreased NAA can be seen in glioma. Lactate peaks found in tumours indicate hypoxia and lipid peaks are clear evidence of necrosis or cell destruction. MRS is very useful in differentiating brain tumours with infections. It can be used to differentiate and diagnose alzheimers disease, ischaemic lesions, hepatic encephalopathy and other metabolic disorders.. MRS is quite useful in locating focal lesions causing epilepsy (Sergio et al, 2003). Prostate MRS can be very helpful in detection of prostate cancer and staging of the disease. It also can be used in assessing the response with radiation treatment and androgen deprivation. After the introduction of endorectal coils, MRS of prostate became more accurate to differentiate prostate cancer from benign prostate hypertrophy (BPH). With the availability of MR systems of higher field strength (>1.5T), MRS of prostate can be done without the endorectal

coil insertion, which is less painful and at the same time without distorting the anatomy of the prostate and rectum. This is crucial for biopsies, prostatectomy or radiotherapy planning. Proton MRS of prostate usually shows a variety of metabolites such as citrate, choline and creatine. In prostatic cancer tissues, the level of citrate is decreased and choline peak will be relatively higher. Usually MRS for prostate is performed using multivoxel technique and the endorectal coil makes it even more difficult for the patient to keep still for 15- 20 minutes for one spectral acquisition (Shields and Price, 2007). Breast MRS for breast is usually performed with single voxel technique and it is useful in distinguishing between malignant and benign lesions. Usually all the active tumours will show elevated levels of choline compounds. By doing MRS of the breast in suspicious lesions, unnecessary biopsies or even mastectomy can be avoided (Bartella et al, 2007). MRI combined with MRS of breast can increase the sensitivity and specificity of MR breast. MRS assist the clinician to obtain a non-invasive biochemical measure of metabolism which influence in the treatment options (Kim et al, 2001). Other Applications Proton MRS can be used to obtain metabolic information from muscles, liver and even from bone marrow. MRS is able to detect intra myocelluar lipids, a metabolite which is involved in the pathogenesis of insulin resistance. Hepatic lipids can be quantified using MRS and spectral characterisation of bone marrow is another advancement in technology (Machann et al, 2008). Phosphorus-31 MR spectroscopy can be used in pediatric liver transplant recipients to assess the status of host related complications after liver transplant(Chu et al, 2005) Future developments The basis of a good quality proton spectrum depends on mainly three developments such as improvements in the hardware (faster gradients, higher field strength, stability and homogeneity of the magnet), acquisition techniques (pulse sequences, RF, full automation of spectral scan and shimming) and improvements in data processing and editing (Koji et al, 2000). Another area to be developed is carbon spectroscopy, which is capable of giving enormous functional information in-vivo (Reusch, 2007). CONCLUSION MRS a non-invasive tool, which allows a series of sampling just like doing multiple biopsies of the same tissue. This is a non-interventional way of getting information from tissues and metabolites (Young and Charles, 1996). Compared to positron emission tomography(PET) and single photon emission computed tomography(SPECT), MRS has become a great tool for clinicians to obtain functional information without exposing the patient to ionising radiation. It can be used to serially monitor biochemical and metabolic changes in progressive diseases such as Alzhiemers disease and BPH. Combination of MRS with MR imaging allows the correlation of anatomical changes with physiology. MRS protocol can be done together with the diagnostic MR imaging and is a robust and clinically well-established technique, which can be used to detect a variety of malignant masses, infections and metabolic disorders. MRS, for radiographer , is a challenge to get a good quality spectrum without any artefacts or patients movement. The technologist must have an in-depth knowledge of functions of the machine and the protocols used for respective clinical conditions. At times , doing MRS can

be tidious, especially prostate spectroscopy with endorectal coil. The person must be competent and familiar with the positioning of endorectal coil to achieve the best signal possible. MRS is a time consuming study, must be repeated several times to obtain a better spectrum if the patient is not co-operative and needs special skills in analysing the spectrum. However, the information gathered non-invasively outweigh all these difficulties. LEARNING OUTCOME AND REFLECTION Personally the study has enabled me to have a better understanding on the technology and advances in the field of MR spectroscopy. Since I am working with MRI and the machine now we have is upgraded with new coils and gradients, with the new software available, whatever I learned from this contract learning , I will be able to a better service to my patients and the hospital. The study was an eye opening experience when I went through several articles and webpages. It allowed me to gain tremendous knowledge in the process of signal formation, acquisition, fourier transform and post processing of the data obtained in MR spectrospy. I have understood the importance of clinical knowledge and competency in order to perform a better spectroscopy scan for my patients. This study gave an opportunity to and read up the details of new developments and techniques in the field of MRI especially MRS.

References

Bartella, L. (2007) Enhancing nonmass lesions in the Breast: Evaluation with Proton (1H) MR Spectroscopy, Radiology, 242(1), pp 60-87. Castillo, M. et al (1996) Clinical Applications of Proton MR Spectroscopy, American Journal of Neuroradiology, 17, pp 1-15. Chary, K.V.R. and Govil, G. (2008) NMR in Biological System. Netherlands: Springer. Chu, W.C.W. et al (2005) Phosphorus-31 mr spectroscopy in pediatric liver transplant recipients: A non-invasive assessment of graft status with correlation with liver function tests and liver biopsy, American journal of radiology, 184, pp 1624-1629. Gillard, J.H. et al (2005) Clinical MR neuroimaging. London: Cambridge University press. Hesselink, J.P. [no date] FUNDAMENTALS OF MR SPECTROSCOPY [online] Available from: http://spinwarp.ucsd.edu/NeuroWeb/Text/mrs-TXT.htm [Accessed 23 Dec 2008] Hoa, D. (2007) Equipment and software required for MRS [online] Available from: http://www.e-mri.org/mr-spectroscopy/equipment-software-mrs.html [Accessed on 12 january 2009] Hornak, J.P. (2007) The Basic of MRI [online] Available from: http://www.cis.rit.edu/htbooks/mri/index.html [Accessed on 12 january 2009] John,R.H.(no date) Fundamentals of MR spectroscopy[online] Available from:

http://spinwarp.ucsd.edu/NeuroWeb/Text/mrs-TXT.htm . [Accesses on 23 December 2008]. Kim, C.M. et al (2001) The evaluation of human breast lesions with magnetic resonance imaging and proton magnetic resonance spectroscopy, Journal of breast cancer research and treatment, 68(1), pp 45-54. Koji,T. et al(2000) MRS of brain and neurological disorders, Japan: CRC press. Kries, R. (2000) H MR Spectroscopy: Clinical Applications [online] Available from: http://www.amsm.dkf.unibe.ch/1-HMRSsyll.pdf. [Accessed 12 Jan 2009] Machann, J. et al (2008) 1H MR spectroscopy of skeletal muscle, liver and bone marrow, European Journal of radiology, 67(2), pp 275-284. McRobbie, D.W. et al (2003) MRI from Picture to Proton, 2nd ed. London: Cambridge University Press. Miner, V.W. and Conover, W.W. (2003) Shimming Part I [online] Available from: http://www.acornnmr.com/Sam/shimintro.htm [Accessed on january 13 2009] MR-T Information Portal (2009) Pulse Sequences [online] Available from: http://www.mrtip.com/serv1.php?type=db1&dbs=Pulse%20Sequence [Accessed 23 Dec 2008] MR-TIP (2009 a) Chemical Shift. [MR-Tip.com] Available from: http://www.mrtip.com/serv1.php?type=db1&dbs=Chemical%20Shift [Accessed 23 Dec 2008] Peggy,W.(ed) (2000) edition 2 MRI for technologists. New York: McGraw-Hill publications Reusch, W. (2007), NMR spectroscopy [online] Available from: http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr1.htm [Accessed on 10 January 2009] Sergio, L.R. et al (2003) proton magnetic resonance spectroscopy: clinical application in patients with brain lesion, Sao Paulo Medical Journal, 121 (6). Shields, A.F. and Price, P. (2007) In Vivo Imaging of Cancer Therapy. Netherlands: Springer. Woodward, P. (2000) MRI for technologists. 2nd ed. New York: McGraw-Hill. Young, I.R. and Charles, H.C. (1996) MR Spectroscopy. London: Informa health care.

Bibliography

John, A. et al (1998) Principles of MRI (2nd edition), Michigan: Appleton and

Lange.

Lindon, J.C. et al (2007) The hand bood of metabonomics, London: Elsevier.

Westbrook, C. et al (1998) MRI in practice (2nd edition), London: Blackwell Publishing Posted by SANTHOSH at 4:26 AM 0 comments

Thursday, February 26, 2009

mr spectroscopy
MAGNETINC RESONANCE SPECTROSCOPY (MRS)

Introduction Magnetic Resonance Imaging or MRI represents a breakthrough in medical diagnostics and research in this century. Its development was one of several powerful imaging techniques that revolutionized medicine by allowing physicians to explore bodily structures and functions. Over the past two decades, advances in the computer technologies coupled with unprecedented growth in the hardware sophistication paved the way for MRI to be most powerful diagnostic tool in modern medicine. In addition to providing exquisite detail of anatomical structures, MRI has evolved to be capable of measuring different metabolite levels in body tissues, the area now known as MR spectroscopy or MRS. In this essay; an attempt is made to understand the underlying principles of MRS and its clinical relevance in diagnostic radiology today.

Magnetic Resonance Imaging (MRI) Magnetic resonance imaging is a technology used primarily in medical settings to produce high quality anatomical images of the human body in any plane without repositioning the patient. MRI is based on the principles of nuclear magnetic resonance (NMR), a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules. The human body is mainly made up of fat and water, which consists of many hydrogen atoms, that makes the human body approximately 63% hydrogen atoms. MRI primarily images the magnetic resonance from the hydrogen nuclei (Hornak, 2007). The principle of nuclear magnetic resonance is based on the fact that, the nuclei of the elements have a magnetic moment and when these are exposed to stronger external magnetic field, these nuclei tends to line up in an angular momentum (precession) with the field. The frequency (Larmor frequency-w0) is equal to the product of the strength of the magnetic field (b0) and a constant called gyro magnetic ratio (l). w0 = l b0 A radio frequency (RF) is then applied to stimulate these lined up protons (in the nuclei) with

the use of a transmitting coil. When the RF is turned off, the protons release energy and go back to the original position. The energy is absorbed and released in a fashion determined by the chemical composition of the particular structure in which the atoms are located. The receiving coils collect the energy released by the protons and a sophisticated computer and display system is used to provide reconstructed images of the structures (Woodward, 2000).

Magnetic Resonance Spectroscopy (MRS) Nuclear magnetic resonance spectroscopy commonly known as Magnetic Resonance Spectroscopy (MRS) is a technology that exploits the magnetic properties of certain nuclei. MRS allows the doctors to obtain biochemical information about the molecules inside the human body without doing a biopsy. So it is also called as in-vivo MRS. In MRI the signals are used to reconstruct an image of the organs whereas in MRS the signals gives a spectrum that contains information about the chemical composition of metabolites in the body. The common nuclei used in MRS are hydrogen (Equals to proton), sodium (Na) and phosphorus (P) and carbon(C). Since hydrogen is abundant in the body tissues, it is easier to perform proton spectroscopy and provides higher signal to noise ratio. The spectroscopy using signals from hydrogen or proton is called proton spectroscopy. Proton spectroscopy can be performed using the same coil that uses for MRI and can be conveniently added on to the routine MRI protocols. The resultant spectra can be used to monitor biochemical changes in tumours, infections, stroke, epilepsy, metabolic disorders and neurodegenerative diseases (Hesselink, no date). Basic physical principles and techniques The resonant frequencies of nuclei, when it is exposed to an external magnetic field, are at the lower end of the electromagnetic spectrum between radio waves and radar waves. The resonant frequencies of protons range between 10 MHz in 0.3 tesla (T) magnetic field and about 300 MHZ on a 7T magnet. This means higher the field strength gives a better signal to noise ratio and better separation between the peaks of different metabolites. The hydrogen atom (proton) exhibits different resonant frequencies in different chemical composition because of the chemical bonding is in various metabolites. The nuclei or protons with different chemical environment show slightly different resonance frequencies given by the equation: w0 = l b0 (1-s) Where s is a screening constant represents the small change in resonance frequency in different molecules which is known as chemical shift. Chemical shift is the basis of MR spectroscopy. s is decided by the molecular structure and the position of proton within the molecule(Honark,2007). The resonance frequencies of the protons are not only affected by the electron clouds surrounded by it, but also due to the interaction between the spins of neighbouring protons, which is known as scalar coupling or spin-spin splitting or J coupling. J coupling can produce splitting of spectral lines into slightly different frequencies for the same proton in a particular metabolite (MR-TIP, 2009 a) The basis of signal production is MRS is similar to MR imaging. Once the patient is placed in the bore of magnet, all the protons will be aligned according to the magnetic field either parallel or anti-parallel direction according to the larmour frequency. Shimming is done to make the magnetic field uniform and a radio frequency pulse is applied, usually a 90 degree pulse, which rotates the protons from z-axis to the x-axis. When the Rf pulse is turned off, the nuclei returns to its original position. The time taken by the nuclei to return to the original

position is according to their relaxation times. The receiving coils placed closer to the body part will detect the energy released by the protons and the voltage variation is called free induction decay. This free induction decay is plotted as an exponential decay function and using fourier transformation, a plot of frequency domain is obtained which shows different larmour frequency at different peaks. The peaks occur at different time intervals for different metabolites. Each peak on the plot or spectral graph depends on the chemical environment of that particular nucleus and usually expressed in Hertz (Hz)(Castillo et al, 1996). In 1.5 tesla MR scanner, the proton spectra of observable metabolites are spread out between 63 to 64 MHz (63-64 million Hz). In order to make the graph more simple, the resonant frequencies are expressed in parts per million (ppm) and the ppm scale reads from right to left (See appendix for the observable proton metabolites in human body). For normal MRI of human body, the signals mainly come from fat and water. If the same signal is used for MRS, the fat and water peaks in the spectrum will be huge and scaling will make it difficult to visualise the signals from the metabolites. So in MRS, we are not interested in the signals from fat and water. Signal from fat is avoided by fat suppression techniques and water suppression is achieved by inversion recovery (IR) or chemical shift selective technique (CHESS). These suppression techniques are used in pulse sequences for obtaining signals from metabolites from the selected part of the body. Pulse sequence is defined as preselected set of defined RF and gradient pulses, usually repeated many times during a scan, wherein the time interval between pulses and the amplitude and shape of the gradient waveforms will control NMR signal reception and affect the characteristics of the MR images. Pulse sequences are computer programs that control all hardware aspects of the MRI measurement process(MR tip, 2009 b). Inhomogeneity in the magnetic field also can affect the spectrum obtained. In order to improve the magnetic homogeneity, shimming must be performed before the spectro scan. Shimming is a process to improve the homogeneity of the magnet by adjusting the direct current (DC) in the gradient coils and the shim coils in the magnet. A homogenous field can improve the sensitivity and resolution of the spectrum (Miner and Conover, 2003). One of the common techniques used in MRS is Single Voxel Spectroscopy (SVS) . In this technique, the main pulse sequences used are spin echo (SE) or point resolved spectroscopy (PRESS) and stimulated echo acquisition method (STEAM). Steam has been widely used in spectroscopy because the content of information regarding the metabolites can be altered according to clinical condition by selecting an appropriate echo time for the sequence (TE)(Chary and Govil, 2008). Another acquisition method used is multivoxel spectroscopy or Chemical Chift Imaging (CSI) (Hesselink, no date). Chemical shift imaging allows metabolite information to be measured in an extended region and to add the chemical analysis of body tissues to the potential clinical utility of MRS. The spatial location is phase encoded and a spectrum is recorded at each phase encoding step to allow the spectra acquisition in a number of volumes covering the whole sample. CSI is useful in mapping of chemical shifts, analogue to individual or more than one spectral lines. The resolutions can be in more than one direction. But the acquisition time for multivoxal spectroscopy is quite long and if the patient moves during the scan, the information obtained may not be ideal for diagnosis. In MRS, the echo time (TE) affects the information obtained. If the TE is short (e.g. 30ms), metabolites with short and long T2 relaxation times can be plotted. With a long TE of 270 ms (millisecond), only those with long T2 relaxation time can be seen. So the radiographer who is doing the scan must be aware of the clinical condition, the metabolites in question and their corresponding relaxation times. A strong and very homogenous magnet is needed to differentiate the resonance peaks of the

metabolites. The resolution and separation in between the metabolites gets better with the strength of the magnet. Specific pulse sequences must be available for signal acquisition together with adapted data processing software (Hoa, 2007). The signal processing comprises of several processing steps such as zero-filling or adaptation filtering to complete the digital signal, phase correction to obtain the actual part of the spectrum and there must be a base line correction available (McRobbie et al, 2007). Poor water suppression or fat suppression will affect the spectral resolution adversely. Saturation bands bands must be placed in all direction to make sure the signals come only from the region of interest. Communication with the patient and patient co-operation is crucial in spectrooscopy scans. Clinical applications In the era of stronger and faster MRI machines, MRS provides a tool to monitor the cellular energy utilization as well as providing other indicators of functional behaviour. MRS can be performed together with the diagnostic MR imaging, so that there is an intrinsic spatial registration between the spectrum and the anatomy. Main clinical applications of MRS can be divided into two categories such as clinical research and clinical routine. Clinical research deals with a group of subjects for a certain reason (for future developments and testing of protocols, coils, software etc). Clinical routine is used in decision making for an individual patient. Proton spectroscopy is widely used in clinical practice today for identifying and diagnosing functional abnormalities and tumours. It also can be used as a tool to pinpoint the location for biopsy and surgical excision of a tumour (Kries, 2000).

Brain The clinical importance of brain MRS depends on the nature and concentration of brain chemicals and the spectrum is analysed in comparison with the MR images. If there is a particular neuro-chemical shows high peaks, the graph must be compared with that of normal brain tissues also. This is a spectral graph of normal brain (Sergio et al, 2003). The metabolites, which can be identified by MRS of brain, are as follows (Gillard et al, 2005). NAA (N-Acetyl Aspartate), ppm 2, a neuronal marker Cr (Creatine), ppm 3&3.9, a marker for energy conversion (ADP-ATP) usually appears in two peaks. Cho (Choline), ppm 3.2, Increased Cho indicated increased membrane synthesis/increased number of cells. Ml (Myo-inositol), ppm 3.6, marker of hormone- inositol diphosphate. Glu & Gln (Glutamate and glutamine- Glx), ppm 2.1-2.5, Neuro transmitter and regulator. Lip (Lipids), ppm 0.9-1.4, an indicator of cell breakdown. Lac (Lactate), ppm 1.3, end product of anaerobic glycolysis. Increased Cho and decreased NAA can be seen in glioma. Lactate peaks found in tumours indicate hypoxia and lipid peaks are clear evidence of necrosis or cell destruction. MRS is very useful in differentiating brain tumours with infections. It can be used to differentiate and diagnose alzheimers disease, ischaemic lesions, hepatic encephalopathy and other metabolic disorders.. MRS is quite useful in locating focal lesions causing epilepsy (Sergio et al, 2003).

Prostate MRS can be very helpful in detection of prostate cancer and staging of the disease. It also can be used in assessing the response with radiation treatment and androgen deprivation. After the introduction of endorectal coils, MRS of prostate became more accurate to differentiate prostate cancer from benign prostate hypertrophy (BPH). With the availability of MR systems of higher field strength (>1.5T), MRS of prostate can be done without the endorectal coil insertion, which is less painful and at the same time without distorting the anatomy of the prostate and rectum. This is crucial for biopsies, prostatectomy or radiotherapy planning. Proton MRS of prostate usually shows a variety of metabolites such as citrate, choline and creatine. In prostatic cancer tissues, the level of citrate is decreased and choline peak will be relatively higher. Usually MRS for prostate is performed using multivoxel technique and the endorectal coil makes it even more difficult for the patient to keep still for 15- 20 minutes for one spectral acquisition (Shields and Price, 2007). Breast MRS for breast is usually performed with single voxel technique and it is useful in distinguishing between malignant and benign lesions. Usually all the active tumours will show elevated levels of choline compounds. By doing MRS of the breast in suspicious lesions, unnecessary biopsies or even mastectomy can be avoided (Bartella et al, 2007). MRI combined with MRS of breast can increase the sensitivity and specificity of MR breast. MRS assist the clinician to obtain a non-invasive biochemical measure of metabolism which influence in the treatment options (Kim et al, 2001). Other Applications Proton MRS can be used to obtain metabolic information from muscles, liver and even from bone marrow. MRS is able to detect intra myocelluar lipids, a metabolite which is involved in the pathogenesis of insulin resistance. Hepatic lipids can be quantified using MRS and spectral characterisation of bone marrow is another advancement in technology (Machann et al, 2008). Phosphorus-31 MR spectroscopy can be used in pediatric liver transplant recipients to assess the status of host related complications after liver transplant(Chu et al, 2005) Future developments The basis of a good quality proton spectrum depends on mainly three developments such as improvements in the hardware (faster gradients, higher field strength, stability and homogeneity of the magnet), acquisition techniques (pulse sequences, RF, full automation of spectral scan and shimming) and improvements in data processing and editing (Koji et al, 2000). Another area to be developed is carbon spectroscopy, which is capable of giving enormous functional information in-vivo (Reusch, 2007). CONCLUSION MRS a non-invasive tool, which allows a series of sampling just like doing multiple biopsies of the same tissue. This is a non-interventional way of getting information from tissues and metabolites (Young and Charles, 1996). Compared to positron emission tomography(PET) and single photon emission computed tomography(SPECT), MRS has become a great tool for clinicians to obtain functional information without exposing the patient to ionising radiation.

It can be used to serially monitor biochemical and metabolic changes in progressive diseases such as Alzhiemers disease and BPH. Combination of MRS with MR imaging allows the correlation of anatomical changes with physiology. MRS protocol can be done together with the diagnostic MR imaging and is a robust and clinically well-established technique, which can be used to detect a variety of malignant masses, infections and metabolic disorders. MRS, for radiographer , is a challenge to get a good quality spectrum without any artefacts or patients movement. The technologist must have an in-depth knowledge of functions of the machine and the protocols used for respective clinical conditions. At times , doing MRS can be tidious, especially prostate spectroscopy with endorectal coil. The person must be competent and familiar with the positioning of endorectal coil to achieve the best signal possible. MRS is a time consuming study, must be repeated several times to obtain a better spectrum if the patient is not co-operative and needs special skills in analysing the spectrum. However, the information gathered non-invasively outweigh all these difficulties. LEARNING OUTCOME AND REFLECTION Personally the study has enabled me to have a better understanding on the technology and advances in the field of MR spectroscopy. Since I am working with MRI and the machine now we have is upgraded with new coils and gradients, with the new software available, whatever I learned from this contract learning , I will be able to a better service to my patients and the hospital. The study was an eye opening experience when I went through several articles and webpages. It allowed me to gain tremendous knowledge in the process of signal formation, acquisition, fourier transform and post processing of the data obtained in MR spectrospy. I have understood the importance of clinical knowledge and competency in order to perform a better spectroscopy scan for my patients. This study gave an opportunity to and read up the details of new developments and techniques in the field of MRI especially MRS.

References

Bartella, L. (2007) Enhancing nonmass lesions in the Breast: Evaluation with Proton (1H) MR Spectroscopy, Radiology, 242(1), pp 60-87. Castillo, M. et al (1996) Clinical Applications of Proton MR Spectroscopy, American Journal of Neuroradiology, 17, pp 1-15. Chary, K.V.R. and Govil, G. (2008) NMR in Biological System. Netherlands: Springer. Chu, W.C.W. et al (2005) Phosphorus-31 mr spectroscopy in pediatric liver transplant recipients: A non-invasive assessment of graft status with correlation with liver function tests and liver biopsy, American journal of radiology, 184, pp 1624-1629. Gillard, J.H. et al (2005) Clinical MR neuroimaging. London: Cambridge University press. Hesselink, J.P. [no date] FUNDAMENTALS OF MR SPECTROSCOPY [online] Available from: http://spinwarp.ucsd.edu/NeuroWeb/Text/mrs-TXT.htm [Accessed 23 Dec 2008]

Hoa, D. (2007) Equipment and software required for MRS [online] Available from: http://www.e-mri.org/mr-spectroscopy/equipment-software-mrs.html [Accessed on 12 january 2009] Hornak, J.P. (2007) The Basic of MRI [online] Available from: http://www.cis.rit.edu/htbooks/mri/index.html [Accessed on 12 january 2009] John,R.H.(no date) Fundamentals of MR spectroscopy[online] Available from: http://spinwarp.ucsd.edu/NeuroWeb/Text/mrs-TXT.htm . [Accesses on 23 December 2008]. Kim, C.M. et al (2001) The evaluation of human breast lesions with magnetic resonance imaging and proton magnetic resonance spectroscopy, Journal of breast cancer research and treatment, 68(1), pp 45-54. Koji,T. et al(2000) MRS of brain and neurological disorders, Japan: CRC press. Kries, R. (2000) H MR Spectroscopy: Clinical Applications [online] Available from: http://www.amsm.dkf.unibe.ch/1-HMRSsyll.pdf. [Accessed 12 Jan 2009] Machann, J. et al (2008) 1H MR spectroscopy of skeletal muscle, liver and bone marrow, European Journal of radiology, 67(2), pp 275-284. McRobbie, D.W. et al (2003) MRI from Picture to Proton, 2nd ed. London: Cambridge University Press. Miner, V.W. and Conover, W.W. (2003) Shimming Part I [online] Available from: http://www.acornnmr.com/Sam/shimintro.htm [Accessed on january 13 2009] MR-T Information Portal (2009) Pulse Sequences [online] Available from: http://www.mrtip.com/serv1.php?type=db1&dbs=Pulse%20Sequence [Accessed 23 Dec 2008] MR-TIP (2009 a) Chemical Shift. [MR-Tip.com] Available from: http://www.mrtip.com/serv1.php?type=db1&dbs=Chemical%20Shift [Accessed 23 Dec 2008] Peggy,W.(ed) (2000) edition 2 MRI for technologists. New York: McGraw-Hill publications Reusch, W. (2007), NMR spectroscopy [online] Available from: http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr1.htm [Accessed on 10 January 2009] Sergio, L.R. et al (2003) proton magnetic resonance spectroscopy: clinical application in patients with brain lesion, Sao Paulo Medical Journal, 121 (6). Shields, A.F. and Price, P. (2007) In Vivo Imaging of Cancer Therapy. Netherlands: Springer. Woodward, P. (2000) MRI for technologists. 2nd ed. New York: McGraw-Hill. Young, I.R. and Charles, H.C. (1996) MR Spectroscopy. London: Informa health care.

Bibliography

John, A. et al (1998) Principles of MRI (2nd edition), Michigan: Appleton and Lange.

Lindon, J.C. et al (2007) The hand bood of metabonomics, London: Elsevier.

Westbrook, C. et al (1998) MRI in practice (2nd edition), London: Blackwell Publishing Posted by SANTHOSH at 6:54 AM 0 comments Older Posts Home Subscribe to: Posts (Atom)