Evaluation of left atrial systolic function in noncompaction cardiomyopathy by real-time three-dimensional echocardiography Background Noncompaction cardiomyopathy -LRB- NCCM -RRB- is a rare disorder with persistance of the embryonic pattern of myoarchitecture . NCCM is characterized by loosened , spongy myocardium associated with a high incidence of systolic and diastolic left ventricular -LRB- LV -RRB- dysfunction and heart failure -LRB- HF -RRB- . It is known that LV dysfunction contributes to elevated left atrial -LRB- LA -RRB- and pulmonary vascular pressures , however atrial function has not been examined in NCCM . The objective of the present study was to assess LA systolic function characterized by LA ejection force -LRB- LAEF -RRB- in NCCM patients using real-time three-dimensional echocardiography -LRB- RT3DE -RRB- and to compare to control subjects . Methods The study comprised 17 patients with an established diagnosis of NCCM and their results were compared to 17 healthy age-matched controls with no evidence of cardiovascular disease . Forty-one percent of NCCM patients were in NYHA functional class II / III HF . Previously proposed echocardiographic diagnostic criteria for NCCM were used . All patients underwent conventional two-dimensional echocardiography and RT3DE . LAEF was measured based on MA annulus diameter -LRB- LAEF3D-MAD -RRB- and area -LRB- LAEF3D-MAA -RRB- using RT3DE . Results The presence and severity of mitral regurgitation were more frequent in NCCM patients than in control subjects . LV diameters and mitral annulus were significantly increased in NCCM patients . Compared with control subjects , both LAEF3D-MAD -LRB- 3.8 ± 2.2 vs 2.3 ± 1.0 kdyne , P < 0.05 -RRB- and LAEF3D-MAA -LRB- 12.7 ± 7.6 vs 4.9 ± 2.1 kdyne , P < 0.01 -RRB- were significantly increased in NCCM patients . Conclusions LAEF as a characteristic of LA systolic function is increased in NCCM patients compared to normal individuals . These results can suggest compensating left atrial work against the dysfunctional LV in NCCM patients . Introduction Noncompaction cardiomyopathy -LRB- NCCM -RRB- is a rare disorder with persistance of the embryonic pattern of myoarchitecture , and has been assumed to occur as a consequence to intrauterine arrest of compaction -LSB- 1 -RSB- . NCCM is characterized by loosened , spongy myocardium associated with a high incidence of systolic and diastolic left ventricular -LRB- LV -RRB- dysfunction and heart failure . It is known that LV dysfunction contributes to elevated left atrial -LRB- LA -RRB- and pulmonary vascular pressures , however atrial function has not been examined in NCCM . It is difficult to assess non-invasively LA contraction , but Manning et al. reported a non-invasive method for the evaluation of LA ejection force -LRB- LAEF -RRB- as a characteristic of LA systolic function -LSB- 2 -RSB- . Anwar et al. demonstrated the usefulness of real-time three-dimensional echocardiography -LRB- RT3DE -RRB- for the evaluation of LAEF -LSB- 3 -RSB- . The objective of the present study was to assess LAEF in NCCM patients using RT3DE and to compare to control subjects . Methods Patient populations The study comprised 17 patients with an established diagnosis of NCCM and their results were compared to 17 healthy age-matched controls with no evidence of cardiovascular disease . All patients and control subjects were in sinus rhytm and all of them were examined by two-dimensional echocardiography -LRB- 2DE -RRB- and RT3DE . Diagnostic criteria for NCCM Previously proposed echocardiographic diagnostic criteria for NCCM by Jenni et al. were used to include patients into the present study from the Outpatient Clinic of Erasmus Medical Center , Rotterdam during 3 years -LSB- 4 -RSB- : -LRB- 1 -RRB- absence of coexisting cardiac anomalies , -LRB- 2 -RRB- segmental , excessive thickening of the LV wall with a two-layered structure : a thin , compacted epicardial layer and a much thicker , noncompacted layer with the characteristic appearance of numerous , prominent trabeculations -LRB- meshwork -RRB- and deep intertrabecular recesses , -LRB- 3 -RRB- colour Doppler evidence of deeply perfused intertrabecular recesses , and -LRB- 4 -RRB- predominant localization of thickening in the LV apical , midlateral , and midinferior walls . Hypertensive heart disease was excluded by clinical and echocardiographic examinations -LRB- septal thickness < 13 mm -RRB- . 2DE examination The 2DE was undertaken with the patient lying in the left lateral decubitus position using both apical and parasternal views . The 2DE studies were performed using a 3.5-MHz transducer and a commercially available ultrasound system -LRB- Sonos 7500 , Philips , Best , The Netherlands -RRB- . The following measures were obtained : -LRB- 1 -RRB- LV end-diastolic diameter -LRB- LV-EDD -RRB- and LV end-systolic diameter -LRB- LV-ESD -RRB- by M-mode echocardiography ; -LRB- 2 -RRB- LV fractional shortening -LRB- LV-FS -RRB- ; -LRB- 3 -RRB- peak velocities of transmitral E and A waves with pulsed Doppler and -LRB- 4 -RRB- mitral regurgitation graded as mild -LRB- jet area < 4 cm2 -RRB- , moderate -LRB- jet area 4 -- 8 cm2 -RRB- , and severe -LRB- jet area > 8 cm2 -RRB- according to maximum jet area by color Doppler . RT3DE examination RT3DE was performed using the same ultrasound system , and performed with a X-4 matrix transducer capable of providing real-time B-mode and colour Doppler . The 3D images were collected within 5 -- 7 s of breath holding in full-volume mode . The 3D data were transferred to an offline analysis system -LRB- TomTec Inc. , Munich , Germany -RRB- . Data were stored digitally and subsequently evaluated by two echocardiographers . Data analysis of RT3DE imaging was based on a two-dimensional approach relying on the echocardiographic images obtained from the apical views and on manual tracing of inner border of the mitral annulus -LRB- MA -RRB- . Once this was completed the surface area was automatically delineated and could be visualized from different points of views . Manual modification was done to correct any image if necessary . The following measures were obtained : -LRB- 1 -RRB- MA diameter -LRB- MAD3D -RRB- and area -LRB- MAA3D -RRB- measured at end-diastole -LRB- just before mitral valve closure -RRB- and -LRB- 2 -RRB- LAEF3D-MAD and LAEF3D-MAA calculated by formula as 0.5 × 1.06 × -LRB- MAD3D or MAA3D -RRB- × V2 , where V is the peak velocity of A wave , 1.06 gm/cm3 is blood viscosity and 0.5 is a coefficient factor -LSB- 2 -RSB- -LRB- Fig. 1 -RRB- . Fig. 1Automatically cropped two-dimensional image from real-time three-dimensional echocardiographic dataset demonstrating left ventricular cavity in a patient with noncompaction cardiomyopathy -LRB- A -RRB- . Measurement of mitral annulus area and mitral inflow A wave velocity can help calculation of left atrial ejection force as a characteristic of atrial systole . Real-time three-dimensional echocardiography allows the ` en-face ` evaluation of mitral annulus helping exact measurement of mitral annulus diameter and area -LRB- B -RRB- . Abbreviations : MA : mitral annulus , MAD : mitral annulus diameter , E and A : mitral inflow E and A wave velocity measured by pulsed Doppler Statistical analysis All data obtained by 2DE or RT3DE were presented as mean ± SD . Data analysis was performed using statistical software -LRB- SPSS , Version 12.1 , SPSS Inc , Chicago , USA -RRB- . Independent sample t test was performed to compare between means of variables of groups to determine the statistical significance of difference . The level of significance was set to p < 0.05 . In our department , an excellent correlation -LRB- r = 0.82 , P < 0.0001 -RRB- has been described between MAD3D and MRI measurements of MAD -LSB- 5 -RSB- . There was no significant difference between MAD3D and MADMRI . Similarly , there was no difference between MAA3D and MAAMRI . Results Clinical and 2D echocardiographic data Clinical and echocardiographic data of NCCM patients and controls are shown in Tables 1 and 2 . The presence and severity of mitral regurgitation were more frequent in NCCM patients than in control subjects . LV diameters were significantly increased , while LV-FS was significantly decreased in NCCM patients . The number of noncompacted segments was 5.4 ± 2.9 in NCCM patients , which did not show any correlation with any echocardiographic parameters . Table 1Demographic and clinical dataParameterNCCM patients -LRB- n = 17 -RRB- Controls -LRB- n = 17 -RRB- Age -LRB- years -RRB- 48 ± 2043 ± 10Male sex -LRB- % -RRB- 8 -LRB- 47 -RRB- 11 -LRB- 65 -RRB- Diabetes mellitus -LRB- % -RRB- 9 -LRB- 53 -RRB- 10 -LRB- 59 -RRB- Hypercholesterolaemia -LRB- % -RRB- 10 -LRB- 59 -RRB- 11 -LRB- 65 -RRB- NYHA-class II/III HF -LRB- % -RRB- 3 -LRB- 18 -RRB- / 4 -LRB- 24 -RRB- 0 -LRB- 0 -RRB- Abbreviations : NCCM : noncompaction cardiomyopathy , NYHA-class II/III HF : New York Heart Association functional class II/III heart failureTable 2Echocardiographic dataParameterNCCM patients -LRB- n = 17 -RRB- Controls -LRB- n = 17 -RRB- 2D echocardiography LV-EDD -LRB- mm -RRB- 60.6 ± 11.0 ** 51.2 ± 6.6 LV-ESD -LRB- mm -RRB- 48.1 ± 13.0 ** 33.0 ± 6.7 LV-FS -LRB- % -RRB- 22.1 ± 17.1 ** 35.7 ± 6.4 Mitral inflow A wave velocity -LRB- cm/s -RRB- 50.1 ± 16.2 * 41.8 ± 9.2 Mitral regurgitation No8 -LRB- 47 -RRB- * 15 -LRB- 88 -RRB- Mild6 -LRB- 35 -RRB- * 2 -LRB- 12 -RRB- Moderate-severe3 -LRB- 18 -RRB- * 0 -LRB- 0 -RRB- RT3DE examination MAD3D -LRB- cm -RRB- 3.5 ± 0.5 * 3.2 ± 0.3 MAA3D -LRB- cm2 -RRB- 12.0 ± 2.8 * 7.9 ± 1.4 LA-EF3D-MAD -LRB- kdyne -RRB- 3.8 ± 2.2 * 2.3 ± 1.0 LA-EF3D-MAA -LRB- kdyne -RRB- 12.7 ± 7.6 ** 4.9 ± 2.1 * P < 0.05 vs controls ** P < 0.01 vs controlsAbbreviations : 2D : two-dimensional , 3D : three-dimensional , A : mitral inflow A wave velocity measured by pulsed Doppler , D : diastolic , EDD : enddiastolic diameter , ESD : endsystolic diameter , FS : fractional shortening , NYHA-class II/III HF : New York Heart Association functional class II/III heart failure , LA-EF : left atrial ejection force , LV : left ventricular , MAA : mitral annulus area , MAD : mitral annulus diameter , NCCM : noncompaction cardiomyopathy RT3DE data Acquisition and postprocessing of RT3DE data were performed successfully with clear delineation of the MA in all patients . Compared with control subjects , MAD3D and MAA3D were significantly larger , while LAEF3D-MAD and LAEF3D-MAA were significantly increased in NCCM patients -LRB- P < 0.05 -RRB- -LRB- Table 2 -RRB- . Discussion Left atrial ejection force -LRB- LAEF -RRB- , based on classic Newtonian mechanics , provides a physiological assessment of atrial systolic function and is a potentially useful index for assessing atrial contribution to diastolic performance . To the best of authors ` knowledge this is the first time to demonstrate increased LAEF during RT3DE indicating high LA workload in NCCM patients . NCCM is known to be a relatively new clinicopathologic entity characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses communicating with the LV cavity -LSB- 1 -RSB- . Results of recent studies confirmed the hypothesis that isolated ventricular noncompaction can be a part of a more widespread cardiomyopathy , involving both the morphologically normal and dysmorphic LV myocardial segments -LSB- 6 -- 9 -RSB- . However , the pathophysiological mechanisms of LV dysfunction remained unclear and , moreover little is known about LA function in NCCM . Manning et al. surmised that LAEF is equal to left ejection volume times acceleration of LA flow according to Newton 's law of motion -LRB- force equals mass times acceleration -RRB- -LSB- 2 -RSB- . Anwar et al. confirmed that RT3DE is a useful method for the evaluation of LAEF3D-MAA -LSB- 3 -RSB- . In recent studies MAA3D has been confirmed to be traced successfully with good interobserver agreement and comparable to magnetic resonance imaging -LSB- 5 -RSB- . RT3DE allowed exact ` en-face ' measurement of MAA3D suggesting overstretching and dilatation in dilated -LSB- 10 -RSB- , hypertrophic -LSB- 3 , 10 -RSB- and noncompaction cardiomyopathy -LRB- present study -RRB- . LAEF was higher in hypertrophic cardiomyopathy -LRB- HCM -RRB- patients compared with control subjects , with the highest value found in patients with obstructive HCM due to higher LV resistance -LSB- 3 -RSB- . LAEF3D-MAA calculated by the MAA3D-derived formula was higher in HCM patients than by the ` mitral valve area ' - derived formula either by 2D echocardiography or RT3DE -LSB- 3 -RSB- . In the present study , 41 % of NCCM patients were in NYHA functional class II / III HF . Recently , Triposkiadis et al. demonstrated that in patients with HF , LAEF and LA kinetic energy are higher than in normal controls -LSB- 11 -RSB- . This is most likely due to LA dilation , which compensates for the depressed LA systolic shortening and increases LA active emptying volume and LA contribution to LV stroke volume , maintaining LV stroke volume and cardiac output -LSB- 11 , 12 -RSB- . However , it should be noted that other authors found decreased LA kinetic energy in patients with advanced HF -LRB- NYHA functional class III HF -RRB- -LSB- 13 , 14 -RSB- . It has been concluded that LA systolic failure contributes to the transition from moderate to advanced HF . Limitations During evaluation of LA systolic function , consideration of other factors affecting LAEF is important . According to recent findings , age considerably influences LAEF -LSB- 15 -RSB- . This fact could also affect our results , but no significant differences were found in age between NCCM patients and controls . LA systolic function is deteriorated in patients with sick sinus syndrome and in those with paroxysmal atrial fibrillation -LSB- 16 -RSB- . However , all of our patients were in sinus rhythm . Cioffi et al. demonstrated that LV geometry can also influence LA size and function -LSB- 17 -RSB- . The concentric LV pattern was associated with the greatest LA volumes and with the strongest LAEF , suggesting that chronic pressure overload more than volume overload stimulates the LA in increasing its workload . Left atrial dilation can be resulted from chronic mitral regurgitation , which can also affect LA systolic function . Another important limitation is that left atrial contraction produces both the forward blood flow toward the LV through the mitral valve and backward flow towards the pulmonary veins . Unfortunately , only the forward blood flow was examined during the present study . Conclusions LAEF is increased in NCCM patients compared to normal individuals . These results can suggest compensating left atrial work against the dysfunctional LV in NCCM patients . However , further studies are warranted evaluating LA function by RT3DE in patients with different stages of NCCM .

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 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 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 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


High incidence of acute lung injury in children with Down syndrome Objective Acute respiratory tract infection is a common reason for hospitalization in children with Down syndrome -LRB- CDS -RRB- and is characterized by a high morbidity . The severe course of disease in CDS may be related to a higher incidence of acute lung injury -LRB- ALI -RRB- . This study evaluated the incidence of ALI and acute respiratory distress syndrome -LRB- ARDS -RRB- in mechanically ventilated CDS . Introduction Down syndrome -LRB- DS -RRB- is the most common chromosomal abnormality and occurs in 1 of 800 live births -LSB- 1 -RSB- . Although survival beyond the first year of life has increased considerably in recent decades , children with DS -LRB- CDS -RRB- still have a shorter life expectancy than those without DS -LSB- 2 -RSB- . Acute respiratory tract infection is a common reason for hospitalization in CDS and is characterized by high morbidity -LSB- 3 -RSB- . In children with DS it has been suggested to be related to pharyngeal incoordination predisposing to aspiration in combination with concomitant immunodeficiencies -LSB- 4 , 5 -RSB- . High morbidity in CDS with respiratory disease may also be related to a higher incidence of acute lung injury -LRB- ALI -RRB- . The aim of this study was to evaluate the incidence of ALI and acute respiratory distress syndrome -LRB- ARDS -RRB- in children with DS who were admitted to the pediatric intensive care unit -LRB- PICU -RRB- and needed mechanical ventilation . Preliminary data from this study were presented at the 35th Congress of the Society of Critical Care Medicine -LSB- 6 -RSB- . Methods This study compared the occurrence of ALI/ARDS in two groups of patients requiring mechanical ventilation because of respiratory insufficiency . The first group consisted of all 24 consecutive children with genetically confirmed DS admitted to our PICU for mechanical ventilation between January 1998 and July 2005 . The second group consisted of all 317 mechanically ventilated children without DS admitted to our PICU between January 1998 and January 2001 . Baseline characteristics for CDS and the control group are shown in Table 1 . The PICU at Emma Children 's Hospital is a 16-bed , tertiary , multidisciplinary unit serving the greater Amsterdam area . Data on the incidence rate of ALI/ARDS in the second group have been published previously -LSB- 7 -RSB- . In both groups patients who were admitted for postoperative care directly following a surgical procedure , and those with a cardiac left to right shunt were excluded . Patients were retrospectively evaluated for ALI/ARDS during the second 24 h after admission according to the American -- European Consensus Conference criteria -LSB- 8 -RSB- . Gas exchange criteria for ALI and ARDS were considered to be met if the PaO2/FIO2 ratio was less than 40.0 kPa for ALI and less than 26.7 kPa for ARDS in at least two consecutive measurements -LRB- > 8 h apart -RRB- . A radiologist blinded to clinical information reviewed the chest radiographs for the presence of bilateral infiltrates . The presence of left heart failure was assessed based on echocardiographic results and/or clinical information . Disease severity on admission was expressed by the Pediatric Risk of Mortality -LRB- PRISM -RRB- II score , which depends on diagnosis and clinical parameters in the first 24 h of admission -LSB- 9 -RSB- . Sepsis was defined as systemic inflammatory response syndrome in the presence of clinical evidence for infection . Lower respiratory tract infection was defined as clinical infection with radiological evidence of alveolar consolidation . Upper respiratory tract infection was defined as infection of the oral and nasal airways , larynx , trachea , and/or bronchi without signs of lower respiratory tract infection . Table 1Baseline patient characteristics and cause for respiratory failureDown syndrome -LRB- n = 24 -RRB- Control group -LRB- n = 317 -RRB- pMedian age -LRB- months ; range -RRB- 15.2 -LRB- 0 -- 127.2 -RRB- 6.1 -LRB- 0 -- 217.7 -RRB- 0.39 cMales14 -LRB- 58.3 % -RRB- 199 -LRB- 62.8 % -RRB- 0.67 dMedian PRISM II score -LRB- range -RRB- 13.5 -LRB- 0 -- 40 -RRB- 9.0 -LRB- 0 -- 47 -RRB- 0.19 cSepsis 3 -LRB- 12.5 % -RRB- 52 -LRB- 16.4 % -RRB- 0.78 eLower respiratory tract infection18 -LRB- 75 % -RRB- 130 -LRB- 41 % -RRB- 0.001 dUpper respiratory tract infection 1 -LRB- 4.2 % -RRB- 23 -LRB- 7.3 % -RRB- 0.96 eCongenital heart disease 1 -LRB- 4.2 % -RRB- 22 -LRB- 6.9 % -RRB- 0.99 eCNS disorders a 0 53 -LRB- 16.7 % -RRB- 0.04 eOther b 1 -LRB- 4.2 % -RRB- 37 -LRB- 11.7 % -RRB- 0.50 eaCNS disorders : convulsions , infections , asphyxia , contusion , cerebral hemorrhage ; bOthers , e. g. , trauma , cardiomyopathies , electrolyte disturbances , metabolic disease ; c Mann -- Whitney test ; d Pearson 's χ2 test ; e Fisher 's exact test The comparability of patient characteristics for both groups was tested by means of a chi-square test or Fisher exact test for dichotomous data and a Mann -- Whitney U test for continuous data that were not normally distributed . The association between DS and ALI/ARDS was expressed as an odds ratio -LRB- OR -RRB- with 95 % Confidence Interval -LRB- CI -RRB- . Other well known cause for ALI/ARDS and thus possible confounders for the incidence of ALI/ARDS among CDS were identified -LSB- 8 , 10 -RSB- and evaluated with bivariate logistic regression analysis . Statistical significance was set at 5 % . Results The criteria for ALI were met in 14 of 24 CDS -LRB- 58.3 % -RRB- and in 41 of 317 controls -LRB- 12.9 % ; odds ratio 9.4 , 95 % confidence interval 3.9 -- 22.6 -RRB- . The criteria for ARDS were met in 11 of 24 CDS -LRB- 46 % -RRB- and in 21 of 317 controls -LRB- 7 % ; odds ratio 11.9 , 95 % confidence interval 4.8 -- 29.8 -RRB- . There were no deaths in the CDS . In the control group ten patients with ALI died during admission to the PICU . The results of the logistic regression analyses are presented in Table 2 . The odds for the incidence of ALI in CDS were hardly altered by adjusting disease severity -LRB- PRISM II score -RRB- , lower respiratory tract infection , or sepsis . Table 2Estimated odds ratio -LRB- OR -RRB- for ALI -LRB- Down/control -RRB- after adjustment for possible confounders -LRB- CI , confidence interval -RRB- Possible confounderOR95 % CINone 9.43.9 -- 22.6 PRISM II score 9.63.9 -- 23.6 Sepsis12 .24.9 -- 30.6 Lower respiratory tract infection10 .84.3 -- 26.9 We excluded patients who died in the first 24 h after admission . This might have caused a selection bias . Therefore PICU deaths during the first 24 h of admission were analyzed for ALI/ARDS : 36 in the control group , none of whom met the ALI/ARDS criteria . No CDS died in the first 24 h after admission . Thus the odds of developing ALI in CDS are about 9 times those in controls , and this can not be attributed to the presence of confounders . Discussion This study found a very high incidence of 58 % of ALI and 46 % of ARDS in mechanically ventilated children with DS . This is significantly higher than the incidence of 13 % of ALI and 7 % of ARDS in the general pediatric population on mechanical ventilation in our unit . Likewise , Randolph et al. -LSB- 11 -RSB- reported an incidence of ARDS of almost 8 % in a mechanically ventilated pediatric population . The results of this study need to be interpreted with caution due to the retrospective design and the relatively low number of CDS . The results need to be confirmed in a prospective multicenter study in a larger cohort . Due to the small number of CDS admitted annually to our unit we included CDS for a longer period of time -LRB- 1998 -- 2005 -RRB- than the control group -LRB- 1998 -- 2001 -RRB- . This may interfere with the comparability of the study groups . However , medical care on our unit did not change substantially during this extended period . In both study periods respiratory care was based on the same clinical protocols with a low tidal volume ventilation strategy . Identical ventilators were used . In addition , the disease severity -LRB- expressed as mean PRISM II scores -RRB- did not differ between 2001 -- 2005 and 1998 -- 2001 . Therefore we have no reason to assume that the incidence of ALI in mechanically ventilated patients changed substantially during the 2001 -- 2005 period . Despite the high incidence of ALI/ARDS we found no mortality in our population of CDS . Others have reported a mortality rate of almost 5 % in children with ARDS -LSB- 11 , 12 -RSB- . Although this remains speculative , it is possible that CDS are more susceptible to progression to ALI/ARDS despite less severe underlying conditions , without concomitant mortality . In addition , there were only three patients with sepsis and none with trauma as underlying cause of ALI/ARDS in the CDS group , conditions associated with a high mortality rate . However , ALI/ARDS is associated with high morbidity in CDS . The need for ventilatory support was 21 ± 21 days in CDS with ALI vs. 8 ± 5 days in CDS without ALI -LRB- p = 0.03 -RRB- . Long-term effects of ALI on morbidity in CDS are unknown and remain to be defined by lung function measurements . The high mortality rate among patients with ALI in the control group might be explained by the relatively high number of patients -LRB- n = 4 -RRB- with severe cerebral damage . This has been shown to be a strong predictor for mortality in ALI -LSB- 13 -RSB- . The mechanism leading to the high incidence of ALI in CDS remains uncertain . Initial ventilator settings have recently been shown to be a risk factor for the development of ARDS -LSB- 14 -RSB- . In this single-center study the ventilatory strategies for CDS did not differ from those in other patients and were based on the same low tidal volume protocol . Recently it has been shown that apoptosis or programmed cell death plays a pivotal role in the pathogenesis of injurious states of the pulmonary system such as of ALI/ARDS -LSB- 15 , 16 -RSB- . The higher incidence of ALI/ARDS may be caused by an elevated rate of apoptosis in CDS . An enhanced level of apoptosis in DS has been shown in several cells including neurons -LSB- 17 , 18 -RSB- , thymocytes -LSB- 19 -RSB- , and granulocytes -LSB- 20 -RSB- . It has been suggested that increased apoptosis in DS cells is related to an inability to deal with oxidative stress , leading to accumulation of reactive oxygen radicals -LSB- 21 -RSB- . One could speculate whether this is related to an imbalance in the antioxidant/oxidant status in patients with DS due to increased levels of superoxide dismutase 1 , an important enzyme in the antioxidant pathway that is encoded for on chromosome 21 -LSB- 22 , 23 -RSB- . To what extent this is associated with an increased susceptibility to develop ALI/ARDS deserves further investigation . From this point of view our findings are not only of scientific interest but may also be of clinical relevance . For example , ventilatory strategies or oxygen therapy might need to be reevaluated and adjusted for CDS . In conclusion , we found an unexpected high incidence of ALI and ARDS in CDS . The explanation for these findings remains to be elucidated .

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

acute respiratory distress syndrome
down syndrome
mechanical ventilation


Do dissociated or associated phoria predict the comfortable prism ? Background Dissociated and associated phoria are measures of latent strabismus under artificial viewing conditions . We examined to what extent dissociated and associated phoria predict the `` comfortable prism '' , i.e. the prism that appears most comfortable under natural viewing conditions . Introduction Since Ogle 's work -LSB- 14 -RSB- dissociated phoria has been distinguished from associated phoria . Dissociated phoria is defined as a deviation from the orthovergence position that occurs when no fusionable contours are provided . Associated phoria is a deviation of the eyes that appears under prism correction of fixation disparity : associated phoria equals the `` aligning prism '' -LSB- 1 -RSB- that nullifies fixation disparity . To avoid the technical requirements for measuring the eye position objectively , fixation disparity is commonly determined according to the observer 's directional perception of monocular Nonius lines , embedded in binocular contours . Both dissociated -LSB- 11 , 18 -RSB- and associated phoria -LSB- 9 , 19 -RSB- have been recommended as indicators for prismatic correction in the case of asthenopia , but recently associated phoria has been preferred , because the stimulus for associated phoria appears to be more natural , in that both eyes are presented with a nearly identical configuration -LSB- 1 , 4 , 5 , 16 , 20 -RSB- . Moreover , Yekta et al. -LSB- 20 -RSB- found the correlation of asthenopic complaints to be significant only with associated , not with dissociated phoria . Kromeier et al. -LSB- 8 -RSB- , however , suggested that dissociated and associated phoria should be similar , provided the accommodative demand in the two procedures is equal . Their argument was based on the consideration that the feedback loop for fusion is opened under both conditions . Concerning dissociated phoria , it is obvious that the feedback loop can not operate ; fusionable contours are absent , hence there is no error signal . Concerning associated phoria , the argument is more complicated because of the fundamental difference between fixation disparity and associated phoria . When the observer looks at a test for fixation disparity , any tendency to deviate from orthoposition is largely kept in check , because the disparity of the binocular contours provides an error signal : the fusional feedback loop is functioning . In the test for associated phoria , however , prisms are added . Prompt and repeated adjustment of the prismatic power nullifies any disparity of fusionable contours . This continuous and artificial resetting of the error signal to zero means that the fusional feedback loop can not fulfill its purpose , namely stabilisation of a certain vergence angle . The experimental results of Kromeier et al. supported their theoretical consideration . These authors suggested that the discrepancies between dissociated and associated phoria encountered in previous studies -LSB- 15 , 20 -RSB- might be due to different accommodative stimuli . To clarify this issue , we compared dissociated and associated phoria using the same object for fixation , thus keeping the accommodative demand similar . We further investigated to what extent dissociated and/or associated phoria predict the `` comfortable prism '' . This term defines the prismatic power reached by the observers when they looked at a fully fusionable display , and tuned a pair of counterrotating prisms , called Herschel 's or Risley 's rotary prisms -LSB- 17 -RSB- , such that the viewing of a fully fusionable object appeared most comfortable . Hence , the comfortable prism anticipated the real-life situation for which prismatic spectacles might be considered . Methods Apparatus Stimuli were generated by a PowerMacintosh G4 and presented at a distance of 4.0 m on a 19 '' Philips GD403 CRT monitor with a resolution of 800 × 600 pixels . By means of liquid crystal shutter goggles -LRB- ELSA 3D Revelator -RRB- , separate images were presented to the two eyes . The goggles were synchronized to the CRT refresh such that the frames were alternately presented to the right and left eyes . The refresh rate was 120 Hz , i.e. 60 Hz for each eye , just above the flicker fusion frequency . The phosphor persistence of the monitor , measured with a photoelectric cell , was down to 10 % after 4.0 ms , i.e. within a shorter time than the frame time of 8 ms. An alternate cover test assured us that this technique provided a complete separation between the images of the two eyes . Herschel 's counterrotating prisms , manufactured by Zeiss , were mounted in front of their right eye -LRB- Fig. 1 -RRB- . Fig. 1Herschel 's prisms mounted in front of the right eye . The observer , looking through shutter goggles , adjusts the prisms by means of a lever arm . A cogwheel belt transmits the prismatic power to a potentiometer These prisms , equipped with a lever arm , allowed a variation of the prismatic power between 30 cm/m base in and 30 cm/m base out . A calibration performed with a laser beam showed that the readings on the scale of the prisms varied only about 2 % around the true inflection . A cogwheel belt connected the prisms with a potentiometer that provided a signal linearly proportional to the prism power . The electric signal was directly transmitted to a computer . During the trials the room was dark ; in the intervals the room was moderately illuminated so that the test person was able to see a coloured print -LRB- Henri Matisse `` Fleurs et céramique '' , 35 × 40 cm , mean luminance 13.8 cd/m2 -RRB- mounted directly above the monitor . Test figures Dissociated phoria As depicted in Fig. 2a , the left eye was presented with a fixation cross , flanked by two O letters -LRB- `` O X O '' -RRB- . Each of the three letters had a diameter of 10 arcmin and a line thickness of 1.5 arcmin . Above and below the cross were two Nonius lines , 20 arcmin high and 5 arcmin wide . The interval between the lines and the centre of the `` O X O '' was 10 arcmin . A bright circular background of 40 arcmin radius , embedded in a random dot pattern , surrounded these dark features . The right eye was presented with a bright dot of 4.3 arcmin diameter on a homogenous dark field . The luminance of the dark features was 0.2 cd/m2 , and that of the bright features 22.6 cd/m2 -LRB- measured through the liquid crystal shutter goggles -RRB- . The luminance outside the monitor was 0.1 cd/m2 . Fig. 2Test figures . a Test for dissociated phoria . All the elements contained in the Mallett figure , including the two Nonius lines , are displayed to the left eye . The right eye is presented with a white dot on a homogenous dark field . b Test for associated phoria , according to Mallett -LSB- 9 -RSB- . c Test for the comfortable prism . An identical figure is displayed to both eyes Associated phoria As depicted in Fig. 2b , the configuration was similar to Mallett 's test for fixation disparity -LSB- 9 -RSB- . The `` O X O '' served as a fusional stimulus . Vertical Nonius lines were used as monocular markers , in that the line above the fixation cross was shown to the right eye , and the line below the fixation cross to the left eye . Comfortable prism Both eyes were presented with all the Mallett elements including both Nonius lines -LRB- Fig. 2c -RRB- . Procedure and instructions The observers were seated in a comfortable chair . During the trials , the observers had to rest their chin on a support , to lean their forehead against a bar , and to adjust Herschel 's prisms with the lever arm . Before each trial , the experimenter set the prisms to ± 0 . To limit prism adaptation -LSB- 12 -RSB- , the time for the adjustment was restricted to 30 seconds . In the interval between the single trials -LRB- about 60 to 120 s -RRB- , the observers were encouraged to move their head freely and to look around in the room or to behold the Matisse painting . Each of the three conditions -LRB- dissociated phoria , associated phoria , comfortable prism -RRB- was tested in a block of eight trials . The conditions were presented in the following order : Associated phoria . If the observers saw an offset between the Nonius lines , they had to align them with the least possible excursion of the lever arm so that they appeared as stable to each other as possible . This instruction resembles the suggestion of Karania and Evens -LSB- 6 -RSB- to observe whether one or both of the Nonius lines ever move . If an observer did not see an offset at the start of the trial , or the Nonius lines oscillated around zero , he or she was encouraged to `` play '' a little with the lever arm and set Herschel 's prisms such that the Nonius lines became aligned as stably as possible . The observers were repeatedly reminded to look at the centre of the `` O X O '' , not at the Nonius lines . Further , the observers were instructed to ignore if one Nonius line , or even if both of them seemed to disappear every now and then -LRB- fading -RRB- . Most observers had such an experience . They had to adjust Herschel 's prisms according to the percept when they saw both Nonius lines.Dissociated phoria . The observers were asked to align the white dot with the midline of the `` O X O '' , neglecting any vertical offset of the white dot . While doing so , they were urged to strictly look at the centre of the `` O X O '' , not at the white dot.Comfortable prism . The observers were asked to look at the centre of the `` O X O '' and to set the prisms such that viewing appeared most relaxing . They were encouraged to start with rather bold searching excursions and to refine the tuning gradually during the available 30 seconds . To get used to the manoeuvring of Herschel 's prisms , the experiment was preceded by a few trials in which the observers practised bringing the white dot to the midline of the `` O X O '' -LRB- test for dissociated phoria -RRB- and aligning the Nonius lines to each other -LRB- test for associated phoria -RRB- . To examine the reproducibility , we repeated the whole experiment for all observers in a second session after an interval of 24 to 130 days . Observers Twenty observers participated in the study -LRB- members of our department or recruits via a public advertisement , aged between 20 and 71 years , median 26.5 years -RRB- . The observers were selected according to the following 4 criteria : -LRB- 1 -RRB- Visual acuity of each eye -LRB- with full spherical and cylindrical correction -RRB- at least 1.0 decimal -LRB- = 6/6Snellen -RRB- , -LRB- 2 -RRB- absence of strabismus , ascertained with the unilateral cover test , -LRB- 3 -RRB- absence of a prism in the spectacles , and -LRB- 4 -RRB- presence of random dot stereopsis -LRB- Lang Test 1 -RRB- . The observers were refracted without dilating their pupils , using streak retinoscopy and crossed cylinders , taking particular care to avoid any uncorrected hyperopia . During the experiment , the observers wore full spherical and cylindrical spectacle corrections . Care was taken to ensure that the glasses remained centred throughout the study . We did not inquire whether the observers had asthenopic symptoms or not . We explained to the observers that the study intended to optimise the comfort of seeing . Otherwise , the observers were kept naive as to the purpose of the study . Each observer provided informed written consent to participate in the experiments . The study followed the tenets of the Declaration of Helsinki and was approved by the institutional human review board . Data acquisition and analysis The prismatic power derived from the potentiometer attached to Herschel 's prisms was recorded by PowerLab with a sampling rate of 100 Hz . To enable analysis of the dynamic behaviour of the adjustments we recorded the full 30 seconds of each trial . Offline examination was accomplished with Igor Pro ® -LRB- Wavemetrics , Inc. , Lake Oswego , OR , USA -RRB- and Statview ® -LRB- Abacus Concepts , Inc. , Berkeley , California , USA -RRB- . Statistical analysis was performed with Statview ® and SPSS ® -LRB- SPSS Inc. , Chicago , Illinois , USA -RRB- . We used multifactorial ANOVA -LRB- including condition , session and trial -RRB- and paired comparisons . For post-hoc tests , Bonferroni adjustment was performed . Results Inspection of curves The curves obtained from the 20 observers varied considerably between the 8 trials . For example see Fig. 3 . There was no trend , e.g. with the early trials -LRB- thin lines -RRB- yielding smaller values than the late ones -LRB- progressively thicker lines -RRB- , or vice versa -LRB- p = 0.34 -RRB- . Most observers adjusted Herschel 's prisms stepwise , reaching the final value after about 20 seconds . Therefore , we limited the numerical evaluation to the remaining 10 seconds . Fig. 3Adjustment of Herschel 's prisms by observer # 10 for dissociated phoria , associated phoria , and the comfortable prism . First session . Positive values indicate base out prisms -LRB- eso deviation -RRB- , negative values base in prisms -LRB- exo deviation -RRB- . The upper panels show the original recordings of the eight single trials . The lower panels show the mean values -LRB- solid lines -RRB- with the standard error of the mean -LRB- SEM , dashed lines -RRB- . Note that the scale of the ordinate for the comfortable prism differs from those in the two phoria conditions For dissociated phoria , most observers saw an offset right at the beginning of each trial and promptly moved the lever arm accordingly . For associated phoria , some observers initially did not see an offset between the Nonius lines . In this case , the observers followed the instruction to `` play '' a little with the lever arm and find a position in which the lines appeared as stable as possible . For the comfortable prism , most observers started with rather bold searching excursions and refined the tuning gradually -LRB- Fig. 3 , right panels -RRB- . Only exceptionally , an observer ended up with a rather large range for the comfortable prism . Statistical analysis We averaged the 1000 values recorded during the last 10 seconds in each of the eight trials , as most observers reached the final value after about 20 seconds . As stated above , there was no trend between the eight trials , e.g. with the early trials yielding smaller values than the late ones , or vice versa -LRB- p = 0.34 -RRB- . This allowed us to treat the 8 trials together and calculate an intertrial mean ± SEM -LRB- standard error of the mean -RRB- for each observer -LRB- Fig. 4 -RRB- . Among the 20 observers , the range of the intertrial mean was for dissociated phoria from +9.3 eso to − 5.9 cm/m exo deviation , for associated phoria from +11.2 eso to − 3.3 cm/m exo deviation , and for the comfortable prism from +4.8 eso to − 4.1 cm/m exo deviation . Fig. 4Mean of the last 10 seconds of eight trials ± SEM for each of the 20 observers . The values obtained in the first session are represented in the left columns , those obtained in the second session in the right columns . DP = dissociated phoria , AP = associated phoria , CP = comfortable prism . The observers are identified with # 1 to # 20 . Ordinate : positive values = eso deviation , negative values = exo deviation . Note that the ordinates in # 7 and # 19 are scaled down To assess the intertrial variability over all 20 observers , we averaged the 95 % confidence interval -LRB- ± 1.96 SD -RRB- per session . The values were as follows . Dissociated phoria : first session ± 1.3 cm/m , second session ± 1.0 cm/m ; associated phoria : first session ± 1.6 cm/m , second session ± 1.6 cm/m ; comfortable prism : first session ± 2.0 cm/m , second session ± 2.2 cm/m . Hence , the variability was similar in the two sessions . Combining the two sessions resulted in a greater overall scatter -LRB- 95 % confidence interval = ± 1.96 SD -RRB- : ± 5.8 cm/m for dissociated phoria , ± 5.4 cm/m for associated phoria , and ± 4.3 cm/m for the comfortable prism . The marked increase in the overall scatter indicates that the values changed between the two sessions . In some cases the mean values of the second session were even outside the 95 % confidence interval of the first session : 5/20 for dissociated phoria , 9/20 for associated phoria , and 6/20 for the comfortable prism . The change was not always concordant in the three conditions . For example , in observer # 13 , the associated phoria changed from +0.1 ± SEM 0.4 cm/m to +4.6 ± SEM 0.5 cm/m , i.e. in the eso direction , and the comfortable prism changed from − 0.1 ± SEM 0.4 cm/m to − 1.8 ± SEM 0.2 cm/m , i.e. in the exo direction . Are these changes clinically relevant ? As several practitioners consider prescribing prisms from a minimum of about 1.0 cm/m onwards -LSB- 13 -RSB- , we identified the observers in whom the change was greater than 1.0 cm/m : for dissociated phoria 6/20 -LRB- up to 3.2 cm/m -RRB- , for associated phoria 11/20 -LRB- up to 4.5 cm/m -RRB- , and for the comfortable prism 12/20 -LRB- up to 3.3 cm/m -RRB- . To find out whether the observers who changed their values by more than 1.0 cm/m could be recognized at the first session , we compared the intertrial variability at the first session in two groups : the observers who changed their values more than 1.0 cm/m with those who changed them less than 1.0 cm/m . There was no statistically significant difference between the two groups -LRB- p = 0.67 for dissociated phoria , 0.11 for associated phoria , 0.52 for the comfortable prism -RRB- . Comparison between dissociated phoria , associated phoria , and the comfortable prism The ANOVA over all trials of all 20 observers -LRB- n = 8 × 2 × 20 = 320 -RRB- revealed that dissociated and associated phoria differed significantly -LRB- p < 0.01 -RRB- . In 11 observers , the dissociated phoria was lower , in four higher than the associated phoria ; in five observers , dissociated and associated phoria were similar . Figure 5 demonstrates that the majority of observers had an eso deviation for dissociated and associated phoria -LRB- 13/20 and 17/20 , respectively -RRB- , but an exo deviation for the comfortable prism -LRB- 17/20 -RRB- . The tendency towards eso deviation in the two phoria conditions was also obvious in the average ± SD over all trials of all 20 observers -LRB- n = 8 × 2 × 20 = 320 -RRB- : +1.0 ± 2.9 cm/m eso deviation for dissociated phoria , and +2.0 ± 2.7 cm/m eso deviation for associated phoria , versus − 0.6 ± 2.2 cm/m exo deviation for the comfortable prism . The difference between dissociated phoria and comfortable prism , on the one hand , and the difference between associated phoria and comfortable prism on the other were both significant -LRB- p < 0.05 and p < 0.001 respectively -RRB- . Fig. 5Mean of the two sessions ± SEM for associated phoria , dissociated phoria , and comfortable prism . The first column in each graph represents observer # 1 , followed by # 2 etc To investigate whether the tendency towards eso deviation in the two phoria conditions , as compared with the comfortable prism , was brought about by the sequence of tests , we made a spot check . We chose observer # 10 , because she had a marked eso deviation in the two phoria conditions , but an exo deviation in the comfortable prism . In an extra session , this observer determined the comfortable prism before the tests for dissociated and associated phoria . The values obtained were of the same magnitude as those in the two previous sessions -LRB- ANOVA p = 0.084 for tested difference -RRB- . Discussion We compared three vergence parameters : dissociated phoria , associated phoria , and the comfortable prism . To avoid any -LRB- possibly prejudiced -RRB- influence of the experimenter , we recorded the prismatic power set by the observer with a potentiometer . The comfortable prism anticipates the real-life situation in which prismatic spectacles are worn . Therefore , the comfortable prism is very close to the endpoint of therapeutical considerations , i.e. prescribing prismatic spectacles . In contrast , dissociated and associated phoria , determined under artificial viewing conditions , are surrogate measures of the comfortable prism . We studied whether these surrogate measures predict the comfortable prism , assuming that dissociated phoria , associated phoria , and the comfortable prism might be similar , because all three parameters are determined by opening the feedback loop for fusional vergence . When measuring dissociated phoria , fusionable contours are absent ; hence , there is no disparity error signal . When associated phoria is measured , any disparity of the -LRB- defective -RRB- fusional pattern , which initially constitutes an error signal , is promptly nullified by repeated prism adjustment . Concerning the comfortable prism , one has to realize that the fusional feedback loop , which uses disparity as its error signal , can stabilize the vergence angle only if the stimuli are presented to the two eyes in a fixed angle , e.g. through a certain unchanging prism . If , however , the observer is asked to adjust a variable prism according to his or her comfort , the fusional feedback loop is open and can not stabilize the vergence angle . Instead , the fusional feedback loop is replaced by another feedback loop whose error signal is discomfort . Accordingly , the vergence position reached with the comfortable prism may also be described as the `` vergence position of rest when both eyes are exposed to identical pictures '' . To our surprise , we found marked differences between the three vergence parameters : as indicated in Fig. 5 , the majority of observers had an eso deviation under the two phoria conditions -LRB- 13/20 for dissociated and 17/20 for associated phoria -RRB- , but preferred base-in for the comfortable prism , corresponding to an exo deviation -LRB- 17/20 -RRB- . The maximal difference occurred in observer # 10 who showed in his second session an eso deviation for associated phoria of +4.9 cm/m , and an exo deviation for the comfortable prism of − 3.0 cm/m . The tendency towards eso deviation in the two phoria conditions was also evident in the significant difference between the averages ± SD over all 20 observers : +1.0 ± 2.9 cm/m eso deviation for dissociated phoria , +2.0 ± 2.7 cm/m eso deviation for associated phoria , but − 0.6 ± 2.2 cm/m exo deviation for the comfortable prism . Although the test condition for associated phoria is commonly regarded as being more natural than that for dissociated phoria , the associated phoria was not closer to the comfortable prism than the dissociated phoria . This means that the difference in the overall luminance for the two eyes , present in our test for dissociated phoria , did not push the vergence away from the value obtained with the comfortable prism . This finding supports the finding of Kromeier et al. -LSB- 7 , 8 -RSB- that unequal luminance of the images for the two eyes does not necessarily influence the vergence position . What is the reason for the tendency towards eso deviation in the two phoria conditions ? A different accommodative demand can be excluded , because we used a similar target in all three conditions . Rather , we suggest that the shift towards eso deviation is brought about by the dissimilarity between the images of the two eyes . This suggestion pertains even to the associated phoria condition , in which ample fusionable contours are available , and the dissimilarity is limited to the monocular Nonius lines . Nevertheless , this dissimilarity was conspicuous for the observers : most of them reported that one or both Nonius lines seemed to disappear every now and then . Correspondingly , the observers reported occasional disappearance of the white dot when they determined their dissociated phoria , although this was less pronounced than the disappearance of the Nonius lines in the associated phoria condition . These observations raise the possibility that the irritating perception of binocular rivalry drives the eso shift in the two phoria conditions . Compatible with this idea is that the eso shift was stronger in the associated than in the dissociated phoria condition , i.e. in the condition with the more pronounced fading . Considering the open feedback loop for fusional vergence in all three conditions , it is not surprising that the values obtained with all three methods -LRB- dissociated phoria , associated phoria , and comfortable prism -RRB- were rather variable . This was true in each of the two sessions . The values changed in many observers from the first to the second session beyond the 95 % confidence interval of the eight trials in the first session . Comparing the three conditions , they did not always change in the same direction -LRB- eso or exo -RRB- . We do not see a specific reason for these changes , as there was no hint that the general health or attentiveness had changed between the two sessions . Rather , the variability might be understandable as there is no need for the ocular motor system to keep the vergence angle stable under open-loop conditions . Surely , adaptation maintains the open-loop vergence in a certain range -LSB- 10 , 12 -RSB- , but this range appears to be rather wide . What are the practical inferences of our study ? As mentioned in the introduction , both dissociated -LSB- 11 , 18 -RSB- and associated phoria -LSB- 9 , 19 -RSB- have been recommended as indicators for prismatic correction in the case of asthenopia . We purposely did not select our observers according to the presence or absence of asthenopic complaints . Rather , we avoided using the relief from asthenopic complaints as a criterion , because this approach would have required prolonged wearing of various test prisms , including placebo , in a controlled design , to face the following four problems . First , a causal relationship between heterophoria and asthenopia is hard to establish , because the prevalence of both conditions is high in the general population , so that an unrelated coincidence can easily occur . Second , wearing prisms for hours or days leads to adaptation , so that the patient may later value even prisms that he or she initially disliked . Third , most asthenopic symptoms are waxing and waning . It is highly likely that patients seek remedy at a time when their symptoms are relatively intense . Hence , a subsequent improvement may well be due to a regression to the mean , rather than to a prism -LSB- 21 -RSB- . Fourth , a relief from symptoms may be brought about by the supportive behaviour of the therapist . Although we did not use the relief from asthenopic complaints as a criterion , we think that our findings relate to the prescription of therapeutic prisms for such patients . The discrepancy between dissociated and associated phoria on the one hand and the comfortable prism on the other hand would probably also occur in patients with asthenopia , and it is plausible to assume that these patients would benefit more from the comfortable prism , chosen by themselves under natural viewing conditions , than from a prescription based on one of the phoria parameters , which carry artefacts due to the artificial test conditions . Another practical aspect of our study is the finding that both phoria parameters and the comfortable prism can change from one session to the next . Are these changes clinically relevant ? Several practitioners consider prescribing prisms from 1.0 cm/m onwards -LSB- 13 -RSB- . On this background , our finding that 12 of the 20 observers changed their comfortable prism by more than 1.0 cm/m -LRB- up to 3.3 cm/m -RRB- within an interval of a few weeks is important . We examined whether patients tending to a long-term change of their open-loop vergence might be identifiable in the first session by a large scatter . Unfortunately , our results did not support this notion : the intertrial variability at the first session was not larger in the observers who changed their values more than 1.0 cm/m , as compared with observers who changed their values less than 1.0 cm/m . Hence , repeated determinations of the comfortable prism on different days appear advisable to identify patients in whom the values remain relatively stable . Only in these patients would a prescription of prisms be reasonable . What are the limitations of our study ? Towards the end of our experiments , we considered that it might have been preferable to randomize the sequence of tests between the 20 observers . However , it is unlikely that such a randomization would have produced significantly different results , for the following two reasons : -LRB- 1 -RRB- an influence of training or fatigue is unlikely since there was no trend between the eight trials of each test , e.g. with the early trials yielding smaller values than the late ones , or vice versa -LRB- p = 0.34 -RRB- , and -LRB- 2 -RRB- a spot check in observer # 10 with the reverse order of tests confirmed this observer 's marked discrepancy between an eso deviation in the two phoria conditions , and an exo deviation in the comfortable prism -LRB- ANOVA p = 0.084 for tested difference -RRB- . The angles encountered in our 20 observers were relatively small : the dissociated phoria ranged from +9.3 cm/m eso to − 5.9 cm/m exo deviation , the associated phoria from +11.2 cm/m eso to − 3.3 cm/m exo deviation , and the comfortable prism from +4.8 cm/m eso to − 4.1 cm/m exo deviation . An extrapolation of our conclusions to observers with larger angles may not be justified . Our tests corresponded to just one of many `` natural '' viewing conditions : with respect to luminance , visual angle , and distance -LRB- 4 meters -RRB- , the conditions were similar to watching television . According to previous work -LSB- 2 , 3 -RSB- , it is likely that , at closer viewing distances , the values would be shifted in the exo direction . Hence , we suggest that the practitioner should determine the comfortable prism in the viewing distance , for which therapeutic prisms are being considered . This recommendation corresponds with the concept of Jaschinski -LSB- 4 -RSB- , who suggested that observers should choose their comfortable viewing distance for computer screens in the real-life situation .

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

heterophoria
fixation disparity
aligning prism
asthenopia