MRI evaluation of tissue iron burden in patients with β-thalassaemia major β-Thalassaemia major is a hereditary haemolytic anaemia that is treated with multiple blood transfusions . A major complication of this treatment is iron overload , which leads to cell death and organ dysfunction . Chelation therapy , used for iron elimination , requires effective monitoring of the body burden of iron , for which serum ferritin levels and liver iron content measured in liver biopsies are used as markers , but are not reliable . MRI based on iron-induced T2 relaxation enhancement can be used for the evaluation of tissue siderosis . Various MR protocols using signal intensity ratio and mainstream relaxometry methods have been used , sometimes with discrepant results . Relaxometry methods using multiple echoes achieve better sampling of the time domain in which relaxation mechanisms take place and lead to more precise results . In several studies the MRI parameters of liver siderosis have failed to correlate with those of other affected organs , underlining the necessity for MRI iron evaluation in individual organs . Most studies have included children in the evaluated population , but MRI data on very young children are lacking . Wider application of relaxometry methods is indicated , with the establishment of universally accepted MRI protocols , and further studies , including young children , are needed . Introduction β-Thalassaemia major is a hereditary anaemia characterized by ineffective erythropoiesis and haemolysis -LSB- 1 -RSB- . The underlying mechanism is defective production of haemoglobin β-chains , resulting in excess of α-chains , which are unstable and precipitate to form intracellular inclusion bodies -LSB- 2 , 3 -RSB- . This excessive intracellular deposition of α-chain material is responsible for accelerated apoptosis of the erythroid precursors and for peripheral haemolysis of the erythrocytes -LSB- 3 -RSB- . By the age of 3 months , severe anaemia develops leading to increased intestinal iron absorption . To maintain haemoglobin at a level of 10 -- 12 g/dl , patients suffering from β-thalassaemia major need to be given repeated blood transfusions -LSB- 1 -RSB- . A major drawback of this treatment is transfusion siderosis , which , in association with the increased intestinal iron absorption , apoptosis of the erythroid precursors and peripheral haemolysis , leads to iron overload -LSB- 1 -RSB- . Iron is ubiquitous in eukaryotic organisms . It is essential for cellular survival and proliferation and for haemoglobin synthesis -LSB- 4 , 5 -RSB- . Human demands for iron are covered partly by intestinal absorption , but mainly from the recycling of iron from old or abnormal erythrocytes phagocytized by macrophages -LSB- 6 -RSB- . Iron released from macrophages binds mainly to transferrin , but also to citrate and albumin to form non-transferrin-bound iron -LRB- NTBI -RRB- which is a toxic form -LSB- 7 -- 9 -RSB- . Extracellular iron bound to transferrin enters the cell via transferrin receptors by a process of endocytosis . Once iron is released into the cytoplasm , it enters a poorly defined cellular compartment termed the labile iron pool -LRB- LIP -RRB- . Iron in this compartment is loosely bound and therefore is highly toxic -LSB- 10 -RSB- . Intracellular iron that is not needed for immediate use is stored in the form of ferritin which consists of an apoprotein storing up to 4,500 atoms of iron -LRB- loading factor 4,500 -RRB- -LSB- 5 , 11 -RSB- , and is not cytotoxic . When ferritin storage capacity is exceeded the LIP increases and haemosiderin is generated from ferritin denaturation -LSB- 10 -RSB- . Iron in the form of haemosiderin is thought to be more cytotoxic -LSB- 10 -RSB- . The iron in the LIP is in both the ferrous -LRB- Fe2 + -RRB- and ferric -LRB- Fe3 + -RRB- forms -LSB- 12 -RSB- . Fe2 + reacts with hydrogen and lipid peroxides and generates highly toxic hydroxyl and lipid radicals -LRB- Fenton reaction -RRB- that damage cellular membranes , proteins and nucleic acids -LSB- 4 -RSB- . Iron overload , just as lack of cellular iron , may lead to cell death and organ dysfunction . Iron overload is a major cause of morbidity and mortality in β-thalassaemia major -LSB- 1 -RSB- . Iron accumulates initially in the reticuloendothelial system -LRB- bone marrow , spleen , liver -RRB- and then in the hepatocytes , the heart -LRB- myocytes -RRB- and the endocrine glands -LSB- 1 , 9 , 13 -RSB- . In contrast to the reticuloendothelial cells , the turnover of iron in the hepatocytes , myocytes and endocrine glands is very low -LSB- 9 -RSB- . Chelation therapy has been used to eliminate excess iron -LSB- 1 , 7 -RSB- . Chelatable iron is derived from the catabolism of haemoglobin in macrophages -LSB- 14 -RSB- . Chelators remove NTBI from the plasma , but they do not interact with ferritin and haemosiderin at clinically relevant rates -LSB- 10 , 15 -RSB- . Desferrioxamine -LRB- DFO -RRB- , which is the chelating agent most widely used over the last 30 years , requires parenteral administration . It removes mainly extracellular iron and only a fraction of the intracellular LIP iron -LSB- 14 , 15 -RSB- . Deferiprone is an oral iron chelator that penetrates the cellular membrane and chelates intracellular species of toxic iron -LSB- 16 -RSB- . Cellular uptake of chelators takes place at different rates in different cells -LSB- 15 -RSB- . DFO is of low toxicity , mainly affecting the optic , auditory and skeletal systems -LSB- 7 -RSB- . Skeletal changes develop mainly due to the toxic effects of DFO on the growth cartilage and are manifested as disproportionate truncal shortening with loss of seated height -LSB- 7 -RSB- . Adverse effects of deferiprone are arthralgia , gastrointestinal symptoms , elevated liver enzymes and rarely agranulocytosis -LSB- 7 , 16 -RSB- . The effective management of patients , and especially of children , with thalassaemia requires optimal monitoring of the toxic effects of both iron overload and excessive chelation therapy . Serum ferritin has been widely used as a surrogate marker and a target ferritin level of 1,000 μg/l is generally recommended -LSB- 7 , 17 -RSB- . However , serum ferritin represents only 1 % of the total iron pool , and as an acute-phase protein it is not specific because the levels can be raised in inflammation -LRB- e.g. hepatitis -RRB- and liver damage -LSB- 7 , 18 , 19 -RSB- . Chronic liver inflammation is not rare in patients with thalassaemia , since over 40 % of them have positive anti-hepatitis C virus -LRB- HCV -RRB- antibodies and more than 50 % have chronic -LRB- persistent or active -RRB- hepatitis -LSB- 20 , 21 -RSB- . Liver iron concentration -LRB- LIC -RRB- measured on needle biopsy is currently considered the gold standard for the evaluation of siderosis -LSB- 7 , 18 , 19 -RSB- . However , needle biopsy is an invasive technique , it is not easily repeatable and the accuracy of the resulting LIC measurement is greatly affected by hepatic inflammation-fibrosis and uneven iron distribution -LSB- 22 -RSB- . Furthermore , it appears that cardiac iron overload , which is the leading cause of death in thalassaemia , can not be predicted from the degree of liver siderosis , probably because of differences in iron kinetics between liver and heart cells -LSB- 9 -RSB- . The use of non-invasive techniques for monitoring iron overload in each of the affected organs would be preferable , and to this end MRI has been used increasingly over the last two decades -LSB- 19 , 22 -- 44 -RSB- . Other non-invasive methodologies are too complex , too costly and not readily available -LRB- i.e. magnetic susceptometry -RRB- , or lack imaging capability -LRB- i.e. magnetic resonance spectroscopy -RRB- -LSB- 45 , 46 -RSB- . MRI assessment of tissue iron Relaxation theories MRI evaluation of tissue iron overload is based on T2 relaxation enhancement induced from the interactions between high-molecular-weight iron complexes such as ferritin , haemosiderin and ferrioxamine with water molecules -LSB- 5 , 47 , 48 -RSB- . Ferrioxamine is produced after cellular uptake of DFO , and in extrahepatic tissues , where there is no active excretion and it may remain for days -LSB- 7 -RSB- . Ferrioxamine-based agents have been used in the past as contrast media because of their T2 * effect -LSB- 49 -RSB- . `` Inner sphere '' and `` outer sphere '' relaxation theories have been proposed to explain the T2 relaxation enhancement induced in siderotic tissues -LSB- 50 -- 55 -RSB- . According to the inner sphere theory , iron electron spins enhance the relaxation of protons of water molecules buried in iron-containing proteins . Enhanced relaxation of the bound water protons is then transferred to the free water protons by water or proton exchange -LSB- 48 , 56 , 57 -RSB- . According to the outer sphere theory , magnetic field gradients induced at the periphery of iron-containing proteins create loss of phase and relaxation enhancement of free water protons diffusing in the neighbourhood -LSB- 53 , 54 -RSB- . MR methodologies MR methods for assessing tissue iron can be separated into two groups : signal intensity ratio -LRB- SIR -RRB- methods and relaxometry methods . Various techniques have been described , including : -LRB- a -RRB- methods measuring SIR based on T2-weighted -LRB- spin-echo -RRB- or T2 * - weighted -LRB- gradient-echo -RRB- sequences -LSB- 19 , 23 -- 26 , 30 , 58 -- 62 -RSB- , -LRB- b -RRB- relaxometry methods measuring absolute T2 , -LRB- c -RRB- relaxometry methods measuring absolute T2 * , and -LRB- d -RRB- hybrid relaxometry methods -LSB- 30 -- 32 , 34 -- 37 , 39 -- 43 , 58 , 63 -RSB- . SIR methods These have been used for the study not only of the liver but also of other organs such as the spleen , pancreas , pituitary gland , bone marrow and abdominal lymph nodes -LSB- 19 , 23 , 25 , 27 , 30 , 58 -- 62 -RSB- . For SIR assessment the signal intensity of the target organ is divided by the signal intensity of a reference tissue -LRB- e.g. fat , muscle -RRB- or noise . Signal intensity measurements are performed in the same slice by using the region-of-interest -LRB- ROI -RRB- method . For large organs such the liver , spleen and pancreas more than one ROI is used , positioned in areas lacking vascular structures and movement artefacts -LSB- 19 , 23 , 25 , 27 , 30 , 58 , 61 , 62 -RSB- . The mean signal intensity from the different ROIs is then divided by the signal intensity of the reference tissue . One ROI is used for signal intensity measurement of the pituitary gland , bone marrow , abdominal lymph nodes and the reference tissue -LSB- 58 -- 60 -RSB- . For SIR evaluation of the liver various reference tissues have been used , of which paraspinal muscle appears to be the best choice because it combines good sensitivity with minimum intersite variability -LSB- 19 , 64 -RSB- . A disadvantage of the SIR methods is that in most cases they use only one echo time -LRB- TE -RRB- and thus lose their detection sensitivity in tissues with heavy siderosis , where transverse relaxation is much faster than the TE . This occurs particularly in the liver at the upper range of LIC values where signal intensities are widely dispersed -LSB- 39 -RSB- . Gandon et al. -LSB- 19 -RSB- , by using an algorithm that combined signal intensity ratios from multiple sequences with different TEs , achieved extension of the detection range up to about 21 mg Fe per gram dry liver tissue , with sensitivity and specificity similar to those of biochemical analysis . T2 relaxometry methods These assess T2 relaxation time or R2 -LRB- 1/T2 -RRB- by using the Carr-Purcell-Meiboom-Gill -LRB- CPMG -RRB- spin-echo sequence , which employs multiple -LRB- 2 -- 32 -RRB- equidistant refocusing 180 ° pulses , each followed by an echo -LSB- 65 , 66 -RSB- . Most scanners , by using a pixel-by-pixel , log-linear fitting model , automatically derive the corresponding T2 maps . Signal intensity measurements in the T2 maps correspond to the mean T2 relaxation time of the included voxels -LSB- 67 -RSB- . To avoid motion artefacts from respiration , studies of abdominal organs should be performed with respiratory triggering . To this end a pressure-sensitive pad is attached to the abdomen and depending on the patient 's respiratory cycle a delay time is chosen . Data acquisition takes place at the end-expiration phase -LSB- 39 , 40 -RSB- . During cardiac MRI , in addition to respiratory triggering , cardiac triggering is necessary . To obtain a minimum repetition time -LRB- TR -RRB- of 2,000 ms two to three R -- R intervals should be allowed between successive excitations -LSB- 39 , 40 -RSB- . The mid-systole phase and a cardiac trigger delay of around 250 -- 300 ms are usually chosen to image the myocardium with sufficient thickness for the best signal intensity measurements -LSB- 39 , 40 -RSB- . A pseudo four-chamber or short-axis view of the heart is generally used . A T2 relaxometry method that received FDA approval for clinical liver iron estimation has recently been developed by St. Pierre et al. -LSB- 44 -RSB- . This method uses multiple T2-weighted single spin-echo sequences with different TEs acquired in half-Fourier mode to reduce acquisition time . The calculated mean R2 values combined with LIC values , obtained from liver biopsies , are used to create calibration curves . T2 * relaxometry methods These evaluate T2 * or R2 * -LRB- 1/T2 * -RRB- by using multiple gradient-echo sequences with different TEs . These methods have been developed to further accelerate acquisition , in order to increase sensitivity and eliminate artefacts related to respiration or cardiac motion . To obtain R2 * -LRB- 1/T2 * -RRB- values , the signal decay curve is usually fitted with an exponential model : S = S0e − TE/T2 * , where S is the net image signal intensity , TE is the echo time and S0 is a constant -LSB- 68 -RSB- . T2 * relaxometry methods have been used mainly for myocardial iron assessment and cardiac gating is always applied -LSB- 35 , 42 , 68 -- 71 -RSB- . Breath-hold sequences have greatly eliminated motion artefacts -LSB- 35 , 42 , 68 -RSB- . Hybrid relaxometry methods Hybrid approaches have been applied in high fields and measure both R2 and R2 * to calculate the inhomogeneity factor R2 ′ = R2 * − R2 -LSB- 34 , 72 , 73 -RSB- . These approaches assume that R2 ′ is more specific to mechanisms of relaxation related to iron than R2 -LSB- 34 , 73 -RSB- . Comparison of the MRI methodologies SIR versus relaxometry SIR methods require shorter acquisition times but lack a wide range of iron assessment -LSB- 63 -RSB- . Relaxometry methods , mainly the T2 * method , by using multiple echoes create in - and out-of-phase effects between water and fat transverse magnetization -LRB- Fig. 1 -RRB- -LSB- 35 -RSB- . Relaxometry methods , although taking longer , are preferable because they achieve a better sampling of the time domain in which relaxation mechanisms take place and lead to more precise results -LSB- 63 -RSB- . Fig. 1A 15-year-old male with β-thalassaemia major . Axial scan with a multiecho gradient-echo sequence -LRB- TR/TE 150/1 .07 , 2.14 , 3.21 , 4.28 , 5.35 , 6.42 , 7.49 , 8.56 , 9.63 , 10.7 , 11.77 , 12.84 , 13.91 , 14.98 , 16.05 , 17.12 , 18.19 , 19.26 , 20.33 , 21.4 ms ; flip angle 35 ° -RRB- . a Second echo shows pixel annulation -LRB- arrows -RRB- due to out-of-phase phenomena , at the interfaces of abdominal organs and muscles with fat . b Fourth echo : no pixel annulation is observed because water and fat protons are in phase -LRB- courtesy of Dr. M. Douskou -RRB- T2 , T2 * and hybrid methods There is no general consensus on which relaxometry method -LRB- spin-echo or gradient-echo -RRB- or index -LRB- R2 , R2 * , R2 ′ -RRB- is best for tissue iron quantification . Theoretically , R2 * and R2 ′ are more sensitive than R2 to iron-induced field inhomogeneities . Gradient-echo sequences evaluating R2 * are preferred for cardiac relaxometry , because of their short acquisition time , but gradient-echo sequences are more prone to artefacts and R2 * is more dependent on factors unrelated to iron , such as susceptibility artefacts from the lungs and the blood oxygenation level-dependent -LRB- BOLD -RRB- effect -LSB- 35 , 74 -RSB- . According to the BOLD effect , the T2 * decreases as the concentration of intracapillary deoxyhaemoglobin increases -LSB- 74 -RSB- . A pronounced BOLD effect may be observed in early diastole and results in signal loss -LSB- 75 , 76 -RSB- . Data collection during mid-systole helps to overcome BOLD effect interference with accurate T2 * measurements of the myocardium . In liver and pituitary studies both T2 and T2 * have been assessed . T2 * is more sensitive to low iron content , but studies in the liver show that these methods suffer from inaccuracies at high iron concentrations -LSB- 77 -RSB- . Furthermore , in high fields susceptibility artefacts from the sphenoid sinus are more pronounced with gradient-echo sequences and may lead to inaccurate measurements of pituitary siderosis -LSB- 43 -RSB- . MRI studies of individual iron overloaded organs The degree of siderosis , the crystalline structure of ferritin , the rate of iron elimination under chelation therapy and the degree of ferrioxamine formation are all organ-specific -LSB- 7 , 15 , 18 , 78 -RSB- . All these parameters may be responsible for differences in the T2 relaxation enhancement induced in the various organs . Individual organs should be considered separately , and the effect of age on iron overload should be taken into account . Higher survival probabilities have been reported in patients with thalassaemia born in the last 30 years -LSB- 79 -RSB- . Patient compliance with treatment regimens and effective chelation therapy are thought to be the main factors associated with improved survival -LSB- 79 -RSB- . The combination of DFO , deferiprone and the new oral chelators is considered very promising , but will require effective monitoring by non-invasive methods -LSB- 80 -RSB- . An increasing number of studies have evaluated iron in the various affected organs by MRI -LSB- 19 , 22 -- 44 -RSB- . Many of these studies have included paediatric patients , but very few have investigated children younger than 10 years and none has included children younger than 5 years -LSB- 17 , 18 , 28 , 39 , 43 , 58 , 60 -- 62 , 77 , 81 -- 84 -RSB- . In addition , very few studies have evaluated the effect of age on individual organ siderosis and only one has evaluated and compared MRI data from younger and older patients with thalassaemia -LSB- 28 , 81 , 82 , 84 -RSB- . Studies have tended to focus on specific organs . Liver For the MRI evaluation of liver siderosis both SIR and relaxometry techniques have been used -LRB- Fig. 2 -RRB- -LSB- 18 , 23 , 28 , 32 , 44 , 68 , 85 -RSB- . R2 of the liver demonstrates a significant positive correlation with serum ferritin and LIC determined from liver biopsy material -LSB- 18 , 23 , 32 , 39 , 40 , 44 , 68 -RSB- . Comparative evaluation of hepatic R2 and R2 * in iron-overloaded patients demonstrates that both parameters correlate closely with LIC -LSB- 85 -RSB- . The relationship of SIR with LIC and serum ferritin varies among studies -LSB- 18 , 30 , 58 -RSB- . In most studies R2 and SIR show a better correlation with LIC than with serum ferritin -LSB- 18 , 23 , 28 , 32 , 44 , 68 , 85 -RSB- . This can be explained in part because the HCV-positive thalassaemia patients in the studies had higher serum ferritin levels than those who were HCV-negative -LSB- 77 , 86 -RSB- . Liver R2 shows no association with the hepatic inflammation histological activity index or the type of hepatitis -LRB- chronic persistent or chronic active -RRB- , but is affected by hepatic fibrosis -LSB- 18 , 39 , 77 -RSB- . Fig. 2A 17-year-old male with β-thalassaemia major . Axial scan , fourth echo of a multiecho spin-echo sequence -LRB- TR/TE : 2000/20 , 40 , 60 , 80 , 100 , 120 , 140 , 160 ms -RRB- , shows low-signal intensity in the liver , bone marrow of the spinal body and the pancreas suggesting iron overload In iron overload states , over 70 % of body iron is found in the liver and LIC has been considered to be the best marker of total body iron burden -LSB- 7 , 18 , 19 -RSB- . Based on the good correlation between hepatic R2 or SIR and LIC a number of recent studies have tested the relationship between siderosis of the liver and other organs -LSB- 28 , 39 , 40 , 58 -- 61 , 87 -RSB- . No correlation has been found between liver and pituitary siderosis -LSB- 28 , 58 -RSB- . With regard to the heart , a correlation with liver siderosis has been found only in cases of heavy myocardial iron deposition -LSB- 39 , 40 -RSB- . This lack of correlation can probably be explained by differences in transferrin receptor concentration , iron kinetics , the crystalline structure of ferritin and the degree of organ inflammation or fibrosis -LSB- 7 , 78 , 88 -- 92 -RSB- . Furthermore , under chelation therapy with DFO intracellular paramagnetic ferrioxamine is formed , which exits slowly from cells unless there is an active excretion pathway as is present in the hepatocytes -LSB- 88 -RSB- . Young patients with thalassaemia studied longitudinally have shown absence of substantial improvement in the MR parameters of liver siderosis under different chelation therapy regimens -LSB- 82 -RSB- . This may be explained by the fact that liver siderosis progresses very fast in thalassaemia patients , and iron overload develops after only 2 years of transfusion therapy -LSB- 93 -RSB- . Therapy with the most widely used chelating agent is started at the age of about 3 years , and until growth is completed DFO should not exceed a dose of 40 mg/kg per day -LSB- 7 -RSB- . An early start to monitoring the progress of tissue iron deposition with MRI might be useful in deciding whether to begin chelation therapy at a younger age and when to introduce new chelating agents . Heart Cardiac failure is the leading cause of death from iron overload in patients with thalassaemia -LSB- 94 , 95 -RSB- . Thalassaemia patients on a regimen of regular blood transfusions who are not receiving chelation therapy , develop heart enlargement by the age of 10 years and heart failure by the age of 16 years -LSB- 22 -RSB- . Cardiomyopathy secondary to iron overload is potentially reversible with vigorous chelation therapy -LSB- 7 -RSB- . Myocardial iron has been evaluated by MRI using SIR and relaxometry techniques -LRB- Fig. 3 -RRB- -LSB- 22 , 28 , 39 , 40 , 68 , 82 , 96 -- 98 -RSB- . In the prechelation era , post-mortem examination of patients with thalassaemia showed a close correlation between cardiac and hepatic iron concentrations . MRI studies have demonstrated discordant results regarding the relationship of myocardial iron with hepatic iron and serum ferritin -LSB- 28 , 39 , 40 , 68 , 97 -RSB- . Differences in iron kinetics and variations in chelation schemes may be responsible for the lack of correlation of the MRI-determined myocardial iron with that of the liver -LSB- 88 -RSB- . More active elimination of iron from the hepatocytes than from the myocytes may play a role in the absence of correlation in patients receiving chelation therapy -LSB- 28 , 39 , 68 -RSB- . Fig. 3A 16-year-old male with β-thalassaemia major . a T2 map of the short axis of the heart shows low values of the left ventricle -LRB- arrow -RRB- and the septum -LRB- arrowhead -RRB- . b R2 * -LRB- = 1/T2 * -RRB- map of the short axis of the heart shows high signal of the septum -LRB- asterisk -RRB- . Note the reduction of motion artefacts and better delineation of the heart boundary in the R2 * image -LRB- courtesy of Dr. M. Douskou -RRB- Another important issue is whether myocardial iron evaluated by MRI could predict which patient will develop cardiac failure and arrhythmia . Thalassaemia patients with significantly reduced left ventricular ejection fraction -LRB- LVEF -RRB- have myocardial T2 * values about 20 ms -LSB- 22 , 37 , 38 , 68 -RSB- , although most patients with T2 * values less than 20 ms have normal LVEF -LSB- 68 -RSB- . Furthermore , the relationship between myocardial R2 and LVEF is either non-existent or weak -LSB- 22 , 38 -- 40 -RSB- . Differences in cardiac functional indices among patients with similar MRI measurement of iron might also be explained by genetic factors that predispose to the more rapid development of cardiac failure when a critical level of myocardial siderosis is reached -LSB- 99 , 100 -RSB- . Heterogeneous iron distribution in the myocardium has been demonstrated in histological studies , and this would suggest the necessity for global MRI estimation of myocardial iron -LSB- 42 , 101 -RSB- . Pepe et al. -LSB- 42 -RSB- , using T2 * multiecho cardiac MRI , demonstrated that global T2 * shows a close correlation with midseptal T2 * , suggesting that the latter may be used for a quick assessment of myocardial siderosis . MR studies have shown that cardiac siderosis increases with age , but that siderosis progresses more slowly in the heart than in the liver -LSB- 28 , 82 -RSB- . Systematic MRI studies in children are necessary in order to evaluate the age at the start of cardiac iron overload . Pituitary gland and brain Increased iron deposition in the anterior pituitary gland is the cause of hypogonadotropic hypogonadism and growth hormone deficiency -LSB- 102 , 103 -RSB- . Iron accumulates in all five cell types of the adenohypophysis , but preferentially in the gonadotropin-secreting cells -LSB- 102 , 103 -RSB- . Gonadotropin cell death due to iron toxicity is probably the cause of the decreased pituitary gland height observed in thalassaemia patients with hypogonadotropic hypogonadism -LRB- Fig. 4 -RRB- -LSB- 104 -RSB- . MRI has been used to evaluate pituitary siderosis with SIR and relaxometry techniques -LSB- 28 , 43 , 83 , 105 -RSB- . SIR and R2 findings show significant correlation with serum ferritin -LSB- 83 -RSB- . The very few studies evaluating simultaneously the pituitary and other solid organs have demonstrated no correlation between their MRI parameters of siderosis -LSB- 28 , 43 , 81 -RSB- . Pituitary siderosis appears to increase with age , but MR data are lacking for children under the age of 7 years -LSB- 28 , 81 -RSB- -LSB- 84 -RSB- . Fig. 4The pituitary . a A 12-year-old male with β-thalassaemia major . Midsagittal T1-weighted -LRB- TR/TE 500/20 ms -RRB- scan shows low-signal intensity of the anterior pituitary lobe -LRB- arrow -RRB- and the bone marrow -LRB- asterisks -RRB- suggesting iron overload . The pituitary gland is small measuring 3.5 mm -LRB- normal for age 5.3 ± 0.8 mm -RRB- -LSB- 112 -RSB- . This patient developed hypogonadotropic hypogonadism . b An 11-year-old male with β-thalassaemia major . Mid-sagittal T1-weighted -LRB- TR/TE 500/20 ms -RRB- scan shows normal signal intensity of the anterior pituitary lobe -LRB- arrow -RRB- along with normal pituitary gland height -LRB- 6 mm -RRB- . The bone marrow -LRB- asterisk -RRB- shows low-signal intensity suggesting iron overload The single study assessing iron in the brain of thalassaemia patients by MRI -LSB- 106 -RSB- showed significantly higher R2 values in the cortex , the putamen and the caudate nucleus in patients than in controls . A lack of correlation between R2 and serum ferritin was found , possibly because serum ferritin , which does not cross the blood -- brain barrier , is not a good marker of brain siderosis -LSB- 106 -RSB- . Pancreas Iron overload leads to impairment of the endocrine and exocrine functions of the pancreas -LSB- 107 , 108 -RSB- . Pancreatic siderosis has been evaluated in thalassaemia patients using SIR techniques and relaxometry techniques -LSB- 61 , 84 , 109 -RSB- . Midiri et al. -LSB- 109 -RSB- , using fat as the reference tissue , found a significant negative correlation of SIR with serum ferritin and trypsin . Papakonstantinou et al. -LSB- 61 -RSB- , using muscle as the reference tissue , found no relationship of the pancreatic SIR with the hepatic SIR or serum ferritin . The findings of Argyropoulou et al. -LSB- 84 -RSB- , using T2 relaxometry techniques , were similar . In addition , relaxometry techniques demonstrated that the T2 relaxation time of the pancreas of patients with thalassaemia is significantly lower in children than in adults -LSB- 84 -RSB- . Fatty degeneration of the pancreas in adult patients may explain these differences -LRB- Fig. 5 -RRB- . Fig. 5Siderosis of the spleen , pancreas and adrenals . a A 14-year-old male with β-thalassaemia major . Axial scan , fourth echo of a multiecho sequence -LRB- TR/TE 2,000 / 20 , 40 , 60 , 80 , 100 , 120 , 140 , 160 ms -RRB- shows low-signal intensity of the liver , pancreas -LRB- arrow -RRB- and spleen suggesting increased iron deposition . b A 27-year-old-male with β-thalassaemia major and diabetes . Axial T2-W -LRB- TR/TE 1,800 / 80 ms -RRB- scan shows low-signal intensity of the liver and adrenals suggesting siderosis . High signal intensity of the pancreas -LRB- arrow -RRB- suggests tissue damage and fatty degeneration Adrenals Abnormalities in adrenal function have been reported in patients with thalassaemia -LSB- 103 -RSB- . There is only one study evaluating adrenals for iron overload with MRI -LRB- Fig. 5 -RRB- , which showed a significant correlation between adrenal and liver siderosis -LSB- 87 -RSB- . Spleen , lymph nodes and bone marrow In spite of the fact that the spleen , lymph nodes and bone marrow , which all contain reticuloendothelial cells , are among the first organs to be affected by iron overload -LSB- 1 , 13 -RSB- , there have been very few studies evaluating their iron overload in thalassaemia by MRI , and these used mainly SIR techniques -LSB- 59 , 60 , 62 , 84 -RSB- . SIR of the spleen shows a significant correlation with serum ferritin but not with SIR of the liver -LRB- Fig. 5 -RRB- -LSB- 62 -RSB- . The absence of correlation between liver and spleen siderosis could be explained by differences in iron kinetics , by differences in the cluster size of iron proteins , by haemochromatosis gene mutations in β-thalassaemia major carriers , and by the presence of extramedullary haemopoietic tissue in the spleen -LSB- 78 , 110 , 111 -RSB- . Intraabdominal lymph nodes in β-thalassaemia have been related to chronic hepatitis C -LSB- 60 -RSB- . Lymph node siderosis correlates with liver , but not with spleen siderosis -LSB- 60 -RSB- . In the few studies that have been reported , SIR and relaxometry methods have shown discordant results for MR parameters of bone marrow siderosis and serum ferritin -LSB- 59 , 84 -RSB- . Normal bone marrow signal associated with liver siderosis has been reported in a few patients with thalassaemia and this may be due to differences in genotype or differences in chelation therapy regimens -LSB- 59 -RSB- . Conclusion It is evident that MR relaxometry has the potential to become the method of choice for non-invasive , safe and accurate assessment of iron load . Further theoretical research , along with studies monitoring wider age groups of patients are needed before a generally accepted protocol can be established . Until then , extreme caution is needed in its clinical application and interpretation . Experimental artefacts , non-optimized protocols , poor data analysis and unawareness of the inherent limitations of current methodologies in assessing a heavy body iron burden can result in misleading diagnosis and inappropriate management of thalassaemia patients with iron overload . Future experimental developments in relaxometry based on a better theoretical understanding of the contribution of the iron-containing proteins to the MR signal are expected to further strengthen its clinical role in the monitoring of patients with β-thalassaemia major .

B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O B O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O B O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O B O O O O O O O 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The neurogenic bladder : medical treatment Neurogenic bladder sphincter dysfunction -LRB- NBSD -RRB- can cause severe and irreversible renal damage and bladder-wall destruction years before incontinence becomes an issue . Therefore , the first step in adequate management is to recognize early the bladder at risk for upper - and lower-tract deterioration and to start adequate medical treatment proactively . Clean intermittent catheterization combined with anticholinergics -LRB- oral or intravesical -RRB- is the standard therapy for NBSD . Early institution of such treatment can prevent both renal damage and secondary bladder-wall changes , thereby potentially improving long-term outcomes . In children with severe side effects or with insufficient suppression of detrusor overactivity despite maximal dosage of oral oxybutynin , intravesical instillation is an effective alternative . Intravesical instillation eliminates systemic side effects by reducing the first-pass metabolism and , compared with oral oxybutynin , intravesical oxybutynin is a more potent and long-acting detrusor suppressor . There is growing evidence that with early adequate treatment , kidneys are saved and normal bladder growth can be achieved in children so they will no longer need surgical bladder augmentation to achieve safe urinary continence in adolescence and adulthood . Introduction Neurogenic bladder sphincter dysfunction -LRB- NBSD -RRB- can develop as a result of a lesion at any level in the nervous system , including the cerebral cortex , spinal cord , or peripheral nervous system . Neurologic conditions in children leading to neurogenic bladder dysfunction are predominantly congenital neural tube defects -LRB- including myelomeningocele , lipomeningocele , sacral agenesis , and occult lesions causing tethered cord -RRB- . Acquired causes such as spinal cord tumors or trauma or sequelae of transverse myelitis are less frequent . Whereas from an etiologic standpoint neurogenic bladder dysfunction is a heterogeneous group , medical management will be similar irrespective of the underlying cause . The vast majority of knowledge about NBSD management comes from long-term experience with myelomeningocele -LRB- MMC -RRB- , the most common neural tube defect . Following the institution of a general treatment policy with advances in neurosurgical and orthopedic treatments in previous decades , governing the associated NBSD has become crucial for improving quality of life and life expectancy in children with neural tube defects . In MMC patients , disordered innervation of the detrusor musculature and external sphincter adversely affects bladder function , which if untreated not only leads to incontinence but also will cause secondary damage and dysfunction of both the upper and lower urinary tracts . Key elements in optimal NBSD management are early diagnosis -LRB- including NBSD typology -RRB- and early -LRB- presymptomatic -RRB- institution of adequate medical treatment . There is indeed growing evidence that management decisions made during infancy , which prevent both renal damage and secondary bladder-wall changes , potentially impact long-term outcomes for renal function and safe urinary continence . After describing the pathophysiology of NBSD and its possible consequences , this paper focuses on diagnosis -LRB- including early identification of patients at risk -RRB- , treatment goals , treatment tools , and practical management of NBSD . Historical evolution The management of NBSD in children has undergone major changes over the years . A first milestone was the introduction of clean intermittent catheterization -LRB- CIC -RRB- in 1972 -LSB- 1 -RSB- . CIC -LRB- combined with anticholinergics if required -RRB- has made `` conservative '' -LRB- medical -RRB- management a successful treatment option , with a good outcome for quality of life and kidney protection . Further important breakthroughs were the wider application of urodynamic testing in the evaluation of infants and young children with suspected NBSD -LSB- 2 -- 4 -RSB- and the better pathophysiological understanding of the natural history of NBSD in patients with spina bifida . In spina bifida , the natural history of the urinary tract in untreated NBSD is one of progressive deterioration by the age of 3 years in up to 58 % of patients -LSB- 5 -RSB- . Several reports have shown this deterioration to be directly related to increased intravesical pressure . In 1981 , the bladder pressure at which urethral leakage occurred was found to be a useful predictor of unsafe bladder function -LSB- 2 -RSB- . The leak-point pressure , as it is now commonly referred to , has become accepted as one of the urodynamic parameters that allows clinicians to differentiate patients with relatively low or high risk for subsequent upper urinary tract deterioration . In 1984 , detrusor external sphincter dyssynergia -LRB- DSD -RRB- was identified as an important factor leading to functional obstruction , and intravesical pressure was recognized as the pathophysiological mechanism of subsequent upper urinary tract deterioration -LSB- 3 -RSB- . Shortly thereafter , urodynamics in infants and children was shown to allow a functional classification of NBSD that correlated with clinical entities of incontinence and obstruction , an approach that has allowed the concept of individualized and presymptomatic therapy in high-risk patients -LSB- 6 -RSB- . Pathophysiology of the neurogenic bladder Under normal conditions , the detrusor muscle , bladder neck , and striated external sphincter function as a synergistic unit for adequate storage and complete evacuation of urine . In healthy bladders , the change in bladder-filling pressure between empty and full is normally less than 10 -- 15 cm H2O . Normal voiding pressures for males and females are from 50 to 80 cm H2O and from 40 to 65 cm H2O , respectively -LSB- 7 -RSB- . In patients with NBSD , disordered innervation of the detrusor musculature and external sphincter adversely affects bladder function . In recent years , it has become clear that children with this condition can be categorized into high - and low-risk groups for secondary damage from a neurogenic bladder based on intravesical pressure . When the detrusor -LRB- filling -RRB- pressure exceeds 40 cm H2O , glomerular filtration rate decreases and pyelocaliceal and ureteral drainage deteriorates , leading to obstructive hydronephrosis and/or vesicoureteral reflux -LSB- 2 , 8 -- 10 -RSB- . Even in the absence of reflux or upper urinary tract dilatation , high intravesical pressure can impair drainage of urine into the bladder . Any pathophysiologic process that causes either intermittent or continuous elevation of bladder pressure above 40 cm H2O places the child at risk for upper urinary tract dysfunction , urinary tract infections , and ultimately renal failure . Intermittent elevation of bladder pressure may occur from detrusor hypertonia , hyperreflexia , or both . Hyperreflexia may cause intermittent elevation of bladder pressure , especially if the external sphincter acts reflexively and tightens rather than relaxes in an attempt to prevent micturition -LSB- detrusor sphincter dyssynergia -LRB- DSD -RRB- -RSB- . Over a long period of time , hyperreflexia with pressures greater than 40 cm H2O may result in detrusor decompensation -LRB- areflexia from myogenic failure -RRB- or in detrusor hypertrophy with associated sacculations and subsequent diverticula formation . These pathophysiologic changes affect the elastic and vesicoelastic properties of the bladder and also result in mechanical ureterovesical junction obstruction . Continuous elevation of bladder pressure above 40 cm H2O may occur from a hypertonic detrusor or a hypertrophic small-capacity bladder secondary to outflow obstruction -LSB- 11 -RSB- . Bladder outlet obstruction is caused by DSD , or by fibrosis of the external urethral sphincter secondary to partial or complete denervation -LSB- 3 , 12 , 13 -RSB- . Bladder outlet obstruction will lead to elevated -LRB- pathologic -RRB- voiding pressures , which will contribute to either detrusor decompensation or hypertrophy . Finally , recurrent urinary tract infections due to bladder residue may aggravate damage to the neurogenic bladder through processes of transmural inflammation and fibrosis . Together with high intravesical pressures and/or vesicoureteral reflux , these lower urinary tract infections will lead to episodes of acute pyelonephritis and irreversible renal damage . Management of the neurogenic bladder General principles and treatment goals The cornerstone of optimal NBSD management is early identification and characterization -LRB- typology -RRB- and the institution of proactive therapy . Crucial for long-term prognosis of patients with NBSD is the fact that the management must start before consequences of bladder dysfunction become apparent . From the outset , the goals of management are to prevent or minimize secondary damage to the upper urinary tracts and bladder from the primary neurogenic bladder dysfunction and to achieve safe social continence -LSB- 14 -RSB- . Thus , long before continence becomes an issue , starting from the first year of life , management is directed at creating a low-pressure reservoir and ensuring complete and safe bladder emptying . Clean intermittent catheterization -LRB- CIC -RRB- or self-catheterization -LRB- CISC -RRB- in combination with anticholinergics -LRB- oxybutynin -RRB- is the standard therapy for children with neurogenic bladder dysfunction with detrusor hyperactivity and/or DSD -LSB- 11 , 15 , 16 -RSB- . This treatment is also feasible and effective in developing countries , where untreated neuropathic bladder is an important cause of preventable chronic renal failure -LSB- 17 , 18 -RSB- . CIC enables complete bladder emptying and thus avoids bladder residues and consequent risks for infections . In the high-risk bladder with DSD , CIC also allows bladder emptying before the occurrence of otherwise `` spontaneous '' high-pressure voiding , which is known to be detrimental for kidney function and drainage . Oxybutynin , a bladder smooth-muscle relaxant , is used to improve bladder dynamics through suppression of detrusor hypertonicity and hyperreflexia . By doing so , oxybutynin eliminates -LRB- high-pressure -RRB- uninhibited detrusor contractions -LRB- and thus urinary leakage -RRB- and prevents high-pressure bladder storage -LRB- due to detrusor hypertonicity or low bladder compliance -RRB- and high-pressure emptying -LRB- in case of DSD -RRB- . Early management , including diagnosis and identification of the high-risk bladder At birth , the majority of patients with neurogenic bladder has normal upper urinary tracts . Without proper management , urinary tract infections and elevated bladder pressures with secondary bladder-wall changes may cause upper urinary tract deterioration within 3 years in up to 58 % -LSB- 5 -RSB- . One third of children who develop impaired kidney drainage do so within the first year of life -LSB- 19 -RSB- . The specific abnormalities vary considerably and are not predicted by the level of the spinal cord defect . Furthermore , the dysfunctional pattern may be dynamic , influenced by spinal cord surgery , tethering , and denervation . In the initial baseline evaluation , clinical observations must be completed with urinalysis -LRB- microscopy and culture -RRB- , renal/bladder ultrasound , and cystourethrogram . These allow the experienced clinician to suspect the type of NBSD and to identify the high-risk subgroup . The next consideration is when to perform urodynamic studies . Two different opinions exist in the literature on the use of urodynamic studies in the early evaluation and further follow-up . In one approach , urodynamic assessment has become an integral part of the initial evaluation and subsequent management , as it allows recognition of the different subtypes of NBSD -LRB- typology -RRB- , proactive interventions , evaluation and guidance of therapy , and early detection of neurologic deterioration -LRB- such as symptomatic tethering of the spinal cord -LSB- 20 -RSB- -RRB- . Advocates justify this approach of routine urodynamics to minimize the deleterious effects of high intravesical pressure by directly measuring it rather than indirectly suspecting it from the development of upper and lower urinary tract changes on serial radiologic imaging . Several studies have shown that early urodynamic evaluation of children with NBSD allows the prediction of which newborns are at risk for upper urinary tract deterioration . Urodynamic risk factors are low bladder compliance , intravesical pressure more than 40 cm H2O , and DSD -LSB- 2 , 3 , 6 , 21 -RSB- . The alternative to urodynamic-based management is serial radiologic imaging to detect secondary evidence of high bladder pressure . Critics of newborn and early infancy urodynamics refer to a lack of standards for performance and interpretation , which might lead to unnecessary interventions -LSB- 22 , 23 -RSB- . Those authors recommend careful history , physical examination , upper urinary tract imaging , and close follow-up during infancy and childhood , reserving urodynamic studies only for patients with evidence of urinary retention on physical examination , new-onset hydronephrosis or febrile urinary tract infection , or for evaluation to achieve continence . Proponents of this approach with selective urodynamics suggest that close monitoring with prompt intervention at first signs of deterioration is effective in protecting the upper urinary tracts -LRB- including preservation of nephrons and thus renal function in the long run -RRB- . A remaining concern , however , could be that in this more expectant approach , high intravesical pressures may have already resulted in irreversible and avoidable damage to the bladder wall , resulting in small-capacity , low-compliance bladders later in life . Although many questions regarding optimal evaluation and management remain unanswered , the consensus on the need of close surveillance , especially in the first years of life , plus the possibility that proactive treatment may be better for the bladder in the very long term , emphasize the need for an integrated approach in which clinical observations , serial imaging , and urodynamics are the basis for early adequate treatment . Urodynamic studies : special considerations in children with NBSD If properly performed , even with possible shortcomings in newborns and infancy , urodynamic studies allow direct diagnosis of NBSD and recognition of dysfunction subtypes . This functional classification allows adequate treatment for the different types and early proactive treatment for the bladder at risk -LSB- 6 -RSB- . It is important for the practitioner to understand the complexities involved in performing urodynamic studies in newborns , infants , and children . Urodynamic assessment can provide reproducible results in newborns and infants , but it requires attention to mechanical factors and filling rates . The younger the child , the higher the risk that mechanical factors -LRB- such as bladder-outlet obstruction by the catheter used for the investigation -RRB- may produce artificial information -LRB- elevated leak pressure or inability to void -RRB- . It has also been shown that using a bladder infusion rate as close as possible to the natural filling rate is important for correct assessment of detrusor properties -LSB- 24 -RSB- . It is presumed that fast infusion rates overcome vesicoelastic detrusor properties , falsely indicating detrusor hypertonicity -LSB- 11 -RSB- . On the other hand , in children who have apparent low-pressure cystograms and who leak during filling -LRB- due to sphincter hypoactivity -RRB- , detrusor hypertonia may be unrecognized -LSB- 25 -RSB- . In these children , it is important to perform a provocative study -LRB- including bladder neck occlusion with a balloon catheter -RRB- to identify unrecognized detrusor hyperactivity prior to bladder-neck surgery for treatment of incontinence . Electromyographic -LRB- EMG -RRB- evaluation of the external urethral sphincter is required to identify DSD . The use of concentric EMG needles is preferred , as it gives more reliable information than patch electrodes -LSB- 11 -RSB- . The combination of X-ray cystography with cystometrogram and sphincter EMG -LRB- video urodynamics -RRB- allows accurate evaluation of the link between intravesical pressure and vesicoureteral reflux and gives direct visual information of -LRB- dys -RRB- synergia between detrusor and sphincter mechanisms -LSB- 26 -RSB- . Clean intermittent catheterisation In children with neurogenic bladder , CIC is the first-choice treatment to empty the bladder adequately -LRB- no residue , no infection -RRB- and safely -LRB- prior to high-pressure voiding -RRB- , and it is a valuable tool for achieving continence . The wide variety of used materials and techniques for CIC does not seem to affect efficacy and safety as long as some basic principles are applied : proper education and training , clean and atraumatic application , and achievement of good patient compliance on a long-term basis . For education , training , and further guidance during follow-up , a dedicated continence nurse is invaluable . Patients and caregivers must understand what is wrong with the bladder/sphincter and why CIC is proposed for treatment , and they have to learn how to catheterize properly . CIC has been successfully used by parents even in newborns and infants , becoming a part of their everyday routine -LSB- 27 -RSB- . Some authors prefer early institution of CIC in all infants with NBSD , given the fact that by the age of 3 years , CIC will be required in all for achieving continence , and given the difficulties of starting CIC at toddler age -LSB- 28 -RSB- . Such early institution of CIC seems to improve family compliance and their ability to assist the child in coping with their disease and with CIC -LSB- 29 -RSB- . CISC can be successfully taught to boys and girls who are motivated and who have developed the required dexterity , mostly around the age of 6 years . The required frequency of catheterization depends on several factors : fluid intake , bladder capacity , and bladder filling/voiding pressures . In practice , it is recommended to catheterize six times a day in infants -LRB- linked with feeding time -RRB- and five times a day in school-aged children . Although reported incidences of CIC-related infection risks are variable , it is generally agreed that the risk is low as long as complete bladder emptying is achieved . Furthermore , reused supplies are not related to more urinary tract infections -LSB- 30 -RSB- . If symptomatic infections occur , these are mainly caused by incomplete bladder emptying , and CIC appliance by child or caregiver needs to be optimized . To prevent urethral strictures and false passage in boys , catheter lubrication and avoidance of forceful manipulation during catheter insertion are advocated . Nonreusable low-friction catheters are considered valuable in high-risk male patients with urethral false passage or very tense sphincters but are unnecessary in routine cases -LSB- 31 -RSB- . To maintain therapeutic compliance with CISC in adolescents , psychosocial support is often required . Neurogenic bowel dysfunction with constipation and fecal soiling can interfere with the institution of a successful CIC treatment . Retained stools may mechanically impair bladder filling , increase detrusor irritability , or contribute to urine retention . Stool incontinence increases the risk of bladder contamination and urinary tract infection . An effective bowel management program is therefore needed . Finally , given the high prevalence of latex allergy -LSB- 32 -RSB- , in the spina bifida population , a strict latex-free approach is of extreme importance . Pharmacologic treatment : anticholinergics Of the anticholinergic agents available , oxybutynin hydrochloride is most commonly used , and long-term experience supports its safety also in newborns and infants -LSB- 33 -RSB- . Oxybutynin is a tertiary amine with a well-documented therapeutic effect on detrusor hyperactivity , and its effectiveness is attributed to a combination of anticholinergic -LRB- M3-selective receptor subtype antagonism -RRB- , antispasmodic , local anesthetic and calcium-channel-blocking activity -LSB- 34 -RSB- . Several studies have shown its efficacy for decreasing the filling pressure , increasing the capacity of the neurogenic bladder , and preserving renal function -LSB- 35 -- 37 -RSB- . The usual dose regimen of oral oxybutynin is 0.3 -- 0.6 mg/kg per day in three doses . In children with insufficient response or significant systemic side effects to oral oxybutynin , intravesical instillation of oxybutynin has been shown to be a highly efficacious , reliable , and well-tolerated therapy for children who would otherwise require surgical therapy -LSB- 38 -- 43 -RSB- . Because a solution suitable for intravesical instillation was not available , crushed oxybutynin tablets were used in the earlier trials , with consequent problems of inconvenience and impracticability , and it was the belief of several authors that poor patient compliance could be resolved by an optimized drug preparation -LSB- 40 , 44 -RSB- . It was subsequently shown that , indeed , eliminating the complex crushing preparation by child or parent makes intravesical oxybutynin therapy easy to use and acceptable for long-term therapy -LSB- 41 -RSB- . The mechanisms underlying the more potent and longer-acting detrusor-suppressive effects of intravesical oxybutyinin , as well as its better tolerability , have been investigated by several groups . It was demonstrated that a reduced first-pass metabolism of oxybutynin after intravesical instillation , resulting in a reduced generation of the N-desethyl metabolite , may explain the clinically relevant reduction of systemic side effects that characterizes intravesical compared with oral oxybutynin therapy -LSB- 45 -RSB- . In addition , these pharmacokinetic studies provided first evidence for a direct local rather than a systemic effect of intravesical oxybutynin on detrusor muscle -LSB- 45 -RSB- . Further evidence for a local effect of intravesically administered oxybutynin was provided by studies showing local -LRB- urothelial -RRB- accumulation , suppression of muscarinic receptor-mediated detrusor muscle contractions , and blocking of muscarinic receptors in bladder-afferent pathways -LSB- 46 , 47 -RSB- . In most reports , intravesical oxybutynin is used in dosages between 0.3 and 0.6 mg/kg per day in two or three doses . Given its better tolerability compared with oral treatment , if required , intravesical dosages can be further increased up to doses of 0.9 mg/kg per day -LSB- 43 -RSB- . To date , the vast majority -LRB- ∼ 90 % -RRB- of patients can be treated successfully with the gold standard treatment of oxybutynin -LRB- oral or intravesical -RRB- and CIC . Other bladder-relaxant drugs include propiverine -LRB- 10 -- 15 mg b.i.d. or t.i.d. , adult dose -RRB- , trospium -LRB- 20 mg b.i.d. , adult dose -RRB- , extended-release oxybutynin , and tolterodine -LRB- children 0.25 -- 1 mg b.i.d. , adults 1 -- 2 mg b.i.d. -RRB- . The current experience with compounds other than oxybutynin is still limited in children with neurogenic bladder -LSB- 48 , 49 -RSB- . Botulinum A toxin injections into the detrusor muscle have been shown to be a potentially valuable approach in the neurogenic overactive bladder -LSB- 50 -RSB- . Repeated botulinum A toxin injections -LRB- as an alternative for or an additive to anticholinergics -RRB- could be considered to postpone or avoid surgical procedures in the small minority of children not responding to standard therapy with CIC and anticholinergics -LSB- 51 -RSB- . However , further investigations are required , given remaining concerns about costs and long-term efficacy and safety of prolonged botulinum A toxin administration . Although some authors have advocated alfa-receptor stimulation of the bladder neck , no validated medical treatment is available to enhance the bladder outlet . Medical management of NBSD in clinical practice Optimal management involves first , early diagnosis , including recognition of high-risk subtypes , and second , proactive institution of adequate treatment . Early proactive treatment of high-pressure dyssynergic lower urinary tracts is important in the long term , not only to preserve renal function -LSB- 52 -RSB- but also to prevent poor bladder compliance and the subsequent need for bladder augmentation -LSB- 35 -RSB- . Urodynamic assessment is used in newborns and infants to come to a functional classification of NBSD , allowing presymptomatic interventions in the high-risk groups and individualized treatment planning according to the type of dysfunction -LSB- 6 , 29 , 53 -RSB- . In clinical practice , four major subtypes can be used to describe NBSD -LRB- Fig. 1 -RRB- : sphincter overactivity combined with detrusor underactivity -LRB- type A -RRB- or overactivity -LRB- type B -RRB- , and sphincter underactivity combined with detrusor underactivity -LRB- type C -RRB- or with detrusor overactivity -LRB- type D -RRB- . The easiest type to treat is type A . This bladder type requires early treatment because of urine retention with high filling pressure and continuous leaking . Here , CIC alone is effective and sufficient and will make the bladder safe and infection free , and the patient will be dry in between -LRB- social continence -RRB- . Good care to empty the bladder totally is most important to avoid bladder infections caused by residual urine . Dysfunctional type B will have high filling and high voiding pressures , being very unsafe from birth onward due to DSD . Here , the act of voiding has to be prevented . With oxybutynin , the overactive detrusor can be `` pharmacologically converted '' to an inactive reservoir -LRB- situation similar to type A -RRB- , which has to be emptied with CIC . In type C , CIC reduces the degree of incontinence and offers much better control over urinary tract infections . To achieve continence , this type will at a later age need surgical intervention on the sphincter -LRB- e.g. sling operation -RRB- . An important caveat here is that detrusor instability may emerge only after surgical improvement of outlet resistance . If this detrusor instability would remain unrecognized and untreated -LRB- with oxybutynin -RRB- , bladder-outlet surgery would have converted a `` wet but safe '' into a `` dry but unsafe '' bladder . In the last dysfunctional subtype -LRB- type D -RRB- , the bladder leaks due to detrusor instability and gradually becomes unsafe due to secondary bladder-wall changes with detrusor hypertrophy and loss of bladder compliance . Therefore , treatment consists of CIC combined with oxybutynin and , at a later age , bladder-outlet surgery . Fig. 1Classification of the neurogenic bladder , with four subtypes -LRB- a -- d -RRB- according to dysfunctional activities of sphincter and detrusor . For each subtype , clinical implications if untreated and principles of management are summarized Once appropriate therapy has been initiated , adequate follow-up is required , with adjustments if needed -LRB- CIC frequency , medication dosing and administration route -RRB- . Treatment efficacy can be assessed using clinical parameters -LRB- including CIC frequency and volume charts -RRB- , urinalysis , renal and bladder ultrasound , X-ray cystography , and video urodynamics . As long-term sequelae of insufficiently treated neurogenic bladders -LRB- renal scarring , noncompliant fibrotic bladder -RRB- already have their origin in the first years of life , the frequency of multidisciplinary follow-up visits must be age dependent -LRB- 3 × yearly up to age 3 years , 2 × yearly in school-aged children , yearly in adults -RRB- . Typically , urinalysis and ultrasound are performed at all visits , cystography to investigate unexpected upper urinary tract infections , and urodynamics periodically to verify that under treatment , the catheterized bladder volumes are age appropriate -LSB- 54 -RSB- and stored under safe pressure conditions -LRB- storage of expected bladder capacity at pressures below 30 cm H2O ; see -LSB- 55 -RSB- -RRB- . With early instituted and optimal treatment , the large majority of patients can be adequately controlled without antireflux surgery or surgical bladder augmentation -LRB- Fig. 2 -RRB- . Augmentation cystoplasty is limited to a small group of patients in whom medical treatment fails -LRB- persistence of high filling pressures -RRB- . In patients with insufficient sphincter activity , continence achievement will require bladder-outlet surgery in addition to medical treatment . In female wheelchair users , surgical intervention to provide a continent stoma will facilitate self-catheterization . Fig. 2Suppression of detrusor hyperactivity with resolution of reflux by nonsurgical management . Illustrative patient with high-risk neurogenic bladder sphincter dysfunction -LRB- NBSD -RRB- -LRB- type B -RRB- , urodynamically showing early unsafe filling pressures -LRB- A -RRB- with high-grade reflux -LRB- a -RRB- and urosepsis before treatment . Under clean intermittent catheterization -LRB- CIC -RRB- plus oxybutynin , the unsafe high-pressure bladder was converted into a safe low-pressure reservoir with good capacity and disappearance of the reflux at control cystography 3 months later -LRB- b -RRB- . Severe systemic side effects , making continuation of oral oxybutynin impossible , disappeared after switching to intravesical oxybutynin . Further urodynamic evaluations -LRB- B : after first intravesical administration ; C : after 4 months -RRB- documented adequate suppression of detrusor hyperactivity -LRB- modified from -LSB- 40 -RSB- -RRB- . Long-term -LRB- currently 13 years -RRB- continuation of CIC and intravesical oxybutynin has resulted in a safe and adequate capacity bladder with social continence for the patient Long-term outcome evaluation and need for life-long follow-up Lifelong follow-up with further periodic investigations of upper urinary tract changes , renal function , and bladder status is extremely important . There are two reasons why long-term outcome evaluation in adulthood and life-long patient follow-up are indispensable . First , for the individual patient , therapy is a life-long requisite , and verifying preservation of the patient 's kidneys is only possible by repetitive assessment throughout adolescence and adulthood . Second , in general , detailed long-term follow-up data will show whether a treatment policy driven by long-term goals is sufficiently effective or requires further adaptations . The effectiveness of efforts preserving upper urinary tract function can only be judged by assessing the ultimate outcome once these patients have reached adolescence or adulthood -LSB- 29 -RSB- . In populations with NBSD , no consensus exists as to how renal status is ideally evaluated -LSB- 56 -RSB- . In clinical practice , upper urinary tract deterioration or protection is often monitored by radiographic images of hydronephrosis and vesicoureteral reflux . Modalities used to look at renal functions include nuclear imaging -LSB- dimercaptosuccinate acid -LRB- DMSA -RRB- renal scan -RSB- , urinary concentrating ability , and glomerular filtration rate assessment . For the latter , creatinine -LRB- Cr -RRB- clearance can be used for patients who are socially continent ; for others , inulin or Cr ethylenediaminetetraacetate -LRB- EDTA -RRB- clearance can be used . Which -LRB- combination -RRB- of these tests is best to evaluate renal function requires further investigation -LSB- 56 -RSB- . Conclusions Medical management with CIC and anticholinergics is effective in preserving renal function and providing safe urinary continence in more than 90 % of patients with a neurogenic bladder . Early diagnosis and treatment institution , long before continence becomes an issue at toddler age , can prevent both renal damage and secondary bladder-wall changes , thereby improving long-term outcomes . Compared with oral oxybutynin , intravesical oxybutynin has more potent and longer-acting detrusor suppressive effects with good tolerance and should be used prior to considering surgical therapies . Therapeutic goals should no longer be restricted to prevention of secondary damage to both upper and lower urinary tracts . Instead , our goal should be to achieve normal renal and bladder growth at safe bladder pressure , with appliance-free continence .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

neurogenic bladder
urinary continence
anticholinergics
intermittent catheterization
urodynamics