Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review.

Introduction: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation.Aim: This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR).Methods: A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted.Results: Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR.Conclusions: Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.

Clinical Monitoring of Sacrococcygeal Teratoma.

BACKGROUND: Sacrococcygeal teratomas (SCT) are often highly vascularized and may result in high-output cardiac failure, polyhydramnios, fetal hydrops, and demise. Delivery is guided by the SCT to fetus volume ratio (SCTratio), SCT growth rate, and cardiac output indexed for weight (CCOi). METHODS: We compared measurements and outcome in 12 consecutive fetuses referred with SCT. Adverse outcomes were: fetal surgery, delivery < 32 gestational weeks or neonatal demise. Only SCTratio and CCOi were used to manage the cases. SCT vascularization index (VI%) was derived from the 3D virtual organ computer-aided analysis (VOCAL) software. The SCTModel (modified from acardiac twins) calculated a hypothetical SCT draining vein size and derived a risk line, using diameters of the superior and inferior vena cava, the azygous and umbilical veins. VI% and a model of systemic and umbilical venous volumes (SCTModel) were tested as indicators for outcome in SCT. RESULTS: Fetuses were monitored from 20.1 to 36.4 gestational weeks and 5/12 had adverse outcomes: 1 had successful open fetal surgery at 23.8 weeks and delivered at term, 4 delivered at < 32 weeks with 3/4 having neonatal demise between 25 and 29 weeks. VI% was significantly higher in cases with adverse outcomes (mean 10.3 [8.9-11.6] vs. 4.4 [3.4-5.3], p < 0.0001). The additional fraction of the fetal cardiac output required to perfuse the SCT-draining vein (XSCO%) (p = 0.46), SCTratio (p = 0.08), and CCOi (p = 0.64) were not significant. All cases with adverse outcome had VI% > 8%. The SCTModel risk line predicted nonadverse outcomes well but lacked data in 2/5 cases with adverse outcomes. CONCLUSIONS: VI% is a significant indicator of SCT cases with adverse outcomes and combined with SCTratio may guide timing of delivery better than current measures.

Periocular CO2 laser resurfacing: severe ocular complications from multiple unintentional laser impacts on the protective metal eye shields.

BACKGROUND AND OBJECTIVES: A 36-year-old woman underwent CO2 laser resurfacing for periocular rhytides using protective stainless steel Cox II ocular shields. Immediately after the treatment, corneal lesions were seen in both eyes. The left eye subsequent developed corneal ulceration and scarring, a deformed iris, cataract, and lower eye lashes showing signs of acute burns. The right cornea had a small inferior mid-peripheral superficial lesion and concomitant lower mid-peripheral burned eye lashes. Our objective was to determine the most likely cause of these ocular complications. STUDY: We estimated temperature-time combinations that could induce corneal injury and cataract. Heat conduction effects from a heated cornea to the lens and from a heated ring of periocular skin to the cornea were computed. The temperature response of a shield following CO2 laser irradiation was determined. RESULTS: We computed that cataract can develop when the corneal temperature reaches, for example, 80 °C for 14 seconds. A periocular ring of heated skin contributes little to the corneal temperature. After 7 pulses of consecutive CO2 laser bursts in 7.5 seconds, the total shield area already reached a homogeneous temperature of 63 °C. CONCLUSION: Despite uncertainties in procedural details and modeling of cataract temperatures, the eye injuries were caused beyond doubt by heating of tear-covered metal eye shields by at least 10 consecutive but unintentional laser impacts. Lasers Surg. Med. 50:980-986, 2018. © 2018 Wiley Periodicals, Inc.

Acardiac twin pregnancies part II: Fetal risk of chorangioma and sacrococcygeal teratoma predicted by pump/acardiac umbilical vein diameters.

BACKGROUND: We recently published pump/acardiac umbilical venous diameter (UVD) ratios, representing the pump twin's excess cardiac output fraction, of 27 acardiac twin pregnancies. There was a clear separation between the 17 pump twins that had life-threatening complications and the 10 that did not. The hypothesis of this study is that placental chorangioma and sacrococcygeal teratoma (SCT), tumors whose perfusion also causes high-output complications, have the same fetal outcome as pump twins when perfusion of the tumor requires the same excess cardiac output fraction. METHODS: We compared the three fetoplacental circulations. Fetuses with a placental chorangioma and acardiac twin pregnancies both have their feeding artery and draining vein located at the placental cord insertion. In contrast, SCT lacks a prescribed feeding artery and draining vein. We, therefore, had to modify our model to assume that the diameter of the hypothetical draining vein is related to the flow difference between inferior vena cava and superior vena cava. The latter flow has been estimated sonographically and is the same as the inferior vena cava flow in the absence of an SCT. Furthermore, a simple modification accounts for the different location of the tumor with respect to the placental cord insertion. RESULTS: We propose to apply the clinical pump/acardiac UVD ratios to pregnancies complicated by placental chorangiomas and the modified pump/acardiac UVD ratios for SCT. CONCLUSION: Risk prediction of these rare fetal tumors may be possible based on application of data on excess cardiac output fractions from pump/acardiac UVD ratios and will require future clinical validation. Birth Defects Research (Part A) 106:733-738, 2016. © 2016 Wiley Periodicals, Inc.

Acardiac twin pregnancies part III: Model simulations.

BACKGROUND: Acardiac monochorionic twins lack cardiac function but grow by passive perfusion of the pump twin's deoxygenated arterial blood through placental arterioarterial (AA) and venovenous (VV) anastomoses and by hypoxia-mediated neovascularization. Pump twins therefore must continuously increase their cardiac output which may cause heart failure. Our aims were: to adapt our twin-twin transfusion syndrome model for acardiac twin pregnancies, to simulate pump and acardiac twin development, and to examine the model for early prognostic markers of pump twin survival. METHODS: We used an infinite acardiac placental resistance, based on placental dye injection studies and simulations, suggesting the AA-Acardiac-VV series resistance determines the pump twin's excess cardiac output. Pump and acardiac development were expressed by the pump's excess cardiac output versus its normal value, represented by pump/acardiac umbilical venous diameter (UVD) ratios. RESULTS: UVD ratios distinguish between AA-VV anastomoses that do and do not cause hydropic pump twins. Pump twins can handle relative larger acardiac perfusion at later than earlier gestation. Both VV and acardiac resistances are significantly smaller than the AA resistance, based on respectively clinical data and acardiac blood volumetric growth. CONCLUSION: Our simulations support clinical results which show that UVD ratios aid in the prediction of pump twin risk. The AA anastomosis controls the future of both the pump and the acardiac. Correlation between acardiac size and pump twin risk is secondary to the AA size but remains clinically usable. These factors may aid in the development of methods for pump twin prognosis and the promotion of selective clinical interventions.Birth Defects Research (Part A), 2016.© 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1008-1015, 2016. © 2016 Wiley Periodicals, Inc.

Hypothesis acardiac twin pregnancies: Pathophysiology-based hypotheses suggest risk prediction by pump/acardiac umbilical venous diameter ratios.

BACKGROUND: A total of 75% of monozygotic twins share 1 monochorionic placenta where placental anastomoses cause several serious complications, for example, acardiac twinning. Acardiac twins lack cardiac function but grow by perfusion of arterial blood from the pump twin. This rare pregnancy has 50% natural pump twin mortality but accurate risk prediction is currently impossible. Recent guidelines suggest prophylactic surgery before 18 weeks, suggesting 50% unnecessary interventions. We hypothesize that (1) adverse pump twin outcome relates to easy-to-measure pump/acardiac umbilical venous diameter (UVD) ratios, representing acardiac perfusion by the pump's excess cardiac output. This hypothesis suggests that (2) UVD-ratios are large, mildly varying in cases without complications but small and decreasing when complications develop, thus predicting that (3) UVD-ratios may allow risk prediction of pump twins. In this exploratory clinical pilot, we tested whether UVD-ratio measurements support these predictions. METHODS: We included 7 uncomplicated (expectant management), 3 elective surgical, and 17 complicated cases (pump decompensation, emergency intervention/delivery or demise). Nine UVD-ratios were measured sonographycally and 18 by pathology. RESULTS: Uncomplicated cases have larger, two serial measurements showing mildly varying UVD-ratios; elective surgical cases show larger UVD-ratios; complicated cases have smaller, two serial measurements showing decreasing UVD-ratios. There were no false-positives, no false-negatives and noncrossing linear trendlines of uncomplicated and complicated cohorts. CONCLUSION: Our data provide first evidence that UVD-ratios allow risk prediction of pump twins. More early uncomplicated and late complicated cases are needed, for example, in a prospective trial, before the separation between uncomplicated and complicated cohorts is accurate enough to support a well-founded decision on (early) intervention.

Acardiac twinning: High resolution three-dimensional reconstruction of a low resistance case.

BACKGROUND: Acardiac twinning is a rare anomaly of monochorionic twin pregnancies. Acardiac fetuses lack a functional heart but are passively perfused by arterial blood from their pump co-twin. Although four acardiac morphological types have been classified, the various paths of anatomical and circulatory acardiac twin development, and the potential influence of acardiac size and perfusion flow as possible predictors of pump twin morbidity and mortality are poorly understood. This report presents the first high resolution three-dimensional reconstruction of the vasculature of an acardiac twin by cryomicrotome imaging. CASE: A small, approximately 7.5-cm-diameter ball-shaped acardius amorphous of 30 5/7 weeks had caused pump twin cardiac decompensation that necessitated an emergency cesarian section. The pump twin survived well. The acardiac body had a partially intact vascular system with large diameter arteries and veins and multiple zones that appeared devoid of perfusion. The three-dimensional reconstruction showed neither recognizable organ structures nor identifiable blood vessels except for the umbilical artery and vein. CONCLUSION: Our case showed a small acardiac mass with large diameter vessels and consequential low outflow resistance that caused pump twin complications. This indicates that the development of a method that allows pump twin prognosis is likely more successful if based on the use of acardiac versus pump twin perfusion flows than on body volume ratios.

Thermal Energy during Irreversible Electroporation and the Influence of Different Ablation Parameters.

PURPOSE: Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE. MATERIALS AND METHODS: IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated. RESULTS: A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C). CONCLUSIONS: Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.

Irreversible electroporation: just another form of thermal therapy?

BACKGROUND: Irreversible electroporation (IRE) is (virtually) always called non-thermal despite many reports showing that significant Joule heating occurs. Our first aim is to validate with mathematical simulations that IRE as currently practiced has a non-negligible thermal response. Our second aim is to present a method that allows simple temperature estimation to aid IRE treatment planning. METHODS: We derived an approximate analytical solution of the bio-heat equation for multiple 2-needle IRE pulses in an electrically conducting medium, with and without a blood vessel, and incorporated published observations that an electric pulse increases the medium's electric conductance. RESULTS: IRE simulation in prostate-resembling tissue shows thermal lesions with 67-92°C temperatures, which match the positions of the coagulative necrotic lesions seen in an experimental study. Simulation of IRE around a blood vessel when blood flow removes the heated blood between pulses confirms clinical observations that the perivascular tissue is thermally injured without affecting vascular patency. CONCLUSIONS: The demonstration that significant Joule heating surrounds current multiple-pulsed IRE practice may contribute to future in-depth discussions on this thermal issue. This is an important subject because it has long been under-exposed in literature. Its awareness pleads for preventing IRE from calling "non-thermal" in future publications, in order to provide IRE-users with the most accurate information possible. The prospect of thermal treatment planning as outlined in this paper likely aids to the important further successful dissemination of IRE in interventional medicine. Prostate 75:332-335, 2015. © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Twin reversed arterial perfusion sequence is more common than generally accepted.

BACKGROUND: Approximately 75% of monozygotic twin pregnancies share one monochorionic placenta where placental anastomoses are virtually always present to connect the two fetoplacental circulations. These anastomoses cause several serious complications such as acardiac twinning. Acardiac twins lack a functional heart but nevertheless show fetal growth because the normal pump twin perfuses the acardiac body through arterioarterial (AA) and venovenous (VV) anastomoses. The widely accepted 1% monochorionic acardiac incidence dates back to 1944 and the associated 1:35,000 pregnancies to 1953. Our aim was to update this analysis. METHODS: We accepted the 1% (actually 1.1%) monochorionic acardiac incidence due to lack of more precise data, included the recently observed 58% early cessation of acardiac development as well as consequences of assisted reproductive technology, and assessed the incidence of acardiac twinning under conditions of AA-VV anastomoses. RESULTS: Early acardiac monochorionic twinning increased from 1.1% to 1.1/(1-0.58) = 2.6%, from 1:35,000 to 1:9,500 to 11,000 pregnancies, depending on number and method of assisted reproductive technology, and occurs in approximately 1:8 AA-VV anastomoses-containing monochorionic placentas. CONCLUSION: Early acardiac twinning is not a rare event. The 1944-based 1% acardiac monochorionic incidence has a weak basis and could therefore be (much) larger. Knowing this incidence more precisely may contribute to our knowledge of embryonic splitting in unequal cell masses.

Ins and outs of endovenous laser ablation: afterthoughts.

Physicists and medical doctors "speak" different languages. Endovenous laser ablation (EVLA) is a good example in which technology is essential to guide the doctor to the final result: optimal treatment. However, for the doctor, it is by far insufficient just to turn on the knobs of the laser. He should understand what is going on in the varicose vein. On the other hand, the physicist is usually not aware what problems the doctor finds on his road towards improving a new technique. We have tried to bring both languages together in the special on Ins and outs of endovenous laser ablation published in this issue of Lasers in Medical Science. The 13 articles include endovenous related clinical (de Roos 2014; Kockaert and Nijsten 2014; van den Bos and Proebstle 2014) and socioeconomical articles (Kelleher et al 2014), the first paper on the molecular pathophysiologic mechanisms (Heger et al 2014), fiber tips (Stokbroekx et al 2014), the future of EVLA (Rabe 2014), a review of EVLA with some important issues for debate (Malskat et al 2014), an excellent paper on transcutaneous laser therapies of spider and small varicose veins (Meesters et al 2014), as well as several scientific modeling articles, varying from a mathematical model of EVLA that includes the carbonized blood layer on the fiber tip (van Ruijven et al 2014) and its application to the simulation of clinical conditions (Poluektova et al 2014) via experimental measurements of temperature profiles in response to EVLA, radiofrequency waves, and steam injections (Malskat et al 2014) to a literature review and novel physics approach of the absorption and particularly scattering properties of whole blood also including the infrared wavelengths used by EVLA (Bosschaart et al 2014). The aim of our afterthoughts, the 14th article in this special, is to try to amalgamate the clinical and physical contents of these contributions, providing the reader with the bridge that overlaps these different backgrounds.

Optical-thermal mathematical model for endovenous laser ablation of varicose veins.

Endovenous laser ablation (EVLA) is successfully used to treat varicose veins. However, the exact working mechanism is still not fully identified and the clinical procedure is not yet standardized. Mathematical modeling of EVLA could strongly improve our understanding of the influence of the various EVLA processes. The aim of this study is to combine Mordon's optical-thermal model with the presence of a strongly absorbing carbonized blood layer on the fiber tip. The model anatomy includes a cylindrically symmetric blood vessel surrounded by an infinite homogenous perivenous tissue. The optical fiber is located in the center of the vessel and is withdrawn with a pullback velocity. The fiber tip includes a small layer of strongly absorbing material, representing the layer of carbonized blood, which absorbs 45% of the emitted laser power. Heat transfer due to boiling bubbles is taken into account by increasing the heat conduction coefficient by a factor of 200 for temperatures above 95 °C. The temperature distribution in the blood, vessel wall, and surrounding medium is calculated from a numerical solution of the bioheat equation. The simulations were performed in MATLAB™ and validated with the aid of an analytical solution. The simulations showed, first, that laser wavelength did virtually not influence the simulated temperature profiles in blood and vessel wall, and, second, that temperatures of the carbonized blood layer varied slightly, from 952 to 1,104 °C. Our improved mathematical optical-thermal EVLA model confirmed previous predictions and experimental outcomes that laser wavelength is not an important EVLA parameter and that the fiber tip reaches exceedingly high temperatures.

Endovascular laser­tissue interactions and biological responses in relation to endovenous laser therapy.

Endovenous laser treatment (ELT) has evolved into a frequently employed modality for the treatment of leg varicose veins. Due to the very high complete response rates, minimal complications and side effects, and the possibility to monitor therapeutic outcome noninvasively by duplex ultrasound, a considerable amount of reports have been published on clinical and translational studies, whereas disproportionally few studies have been performed to elucidate the molecular and cellular basis for post-ELT vessel obliteration. Consequently, this review addresses the putative molecular and cellular mechanisms responsible for varicose vein obliteration following laser irradiation in the context of endovenous laser­tissue interactions. First, the histological profile of laser-treated varicose veins is summarized, and an account is given of the temporal and spatial dynamics of cells involved in inflammation and remodeling in the heat-affected vein segment. Inasmuch as thrombotic occlusion of the venous lumen blocks circulatory access to the affected vessel segment and thermal damage in the vascular wall causes most cells to die, the majority of cells involved in inflammation and remodeling have to be recruited. Second, the (possible) biochemical triggers for the chemotactic attraction of immune cells and fibroblasts are identified, comprising (1) thermal coagula, (2) thrombi, (3) dead and dying cells in the vein wall, and (4) thermally denatured extracellular matrix proteins in the vein wall. The molecular biology underlying the chemotactic signaling and subsequent obliterative remodeling is elucidated. Finally, the relative contribution of every biochemical trigger to obliterative remodeling is addressed.

Some controversies in endovenous laser ablation of varicose veins addressed by optical-thermal mathematical modeling.

Minimally invasive treatment of varicose veins by endovenous laser ablation (EVLA) becomes more and more popular. However, despite significant research efforts performed during the last years, there is still a lack of agreement regarding EVLA mechanisms and therapeutic strategies. The aim of this article is to address some of these controversies by utilizing optical-thermal mathematical modeling. Our model combines Mordon's light absorption-based optical-thermal model with the thermal consequences of the thin carbonized blood layer on the laser fiber tip that is heated up to temperatures of around 1,000 °C due to the absorption of about 45% of the laser light. Computations were made in MATLAB. Laser wavelengths included were 810, 840, 940, 980, 1,064, 1,320, 1,470, and 1,950 nm. We addressed (a) the effect of direct light absorption by the vein wall on temperature behavior, comparing computations by using normal and zero wall absorption; (b) the prediction of the influence of wavelength on the temperature behavior; (c) the effect of the hot carbonized blood layer surrounding the fiber tip on temperature behavior, comparing wall temperatures from using a hot fiber tip and one kept at room temperature; (d) the effect of blood emptying the vein, simulated by reducing the inside vein diameter from 3 down to 0.8 mm; (e) the contribution of absorbed light energy to the increase in total energy at the inner vein wall in the time period where the highest inner wall temperature was reached; (f) the effect of laser power and pullback velocity on wall temperature of a 2-mm inner diameter vein, at a power/velocity ratio of 30 J/cm at 1,470 nm; (g) a comparison of model outcomes and clinical findings of EVLA procedures at 810 nm, 11 W, and 1.25 mm/s, and 1,470 nm, 6 W, and 1 mm/s, respectively. Interestingly, our model predicts that the dominating mechanism for heating up the vein wall is not direct absorption of the laser light by the vein wall but, rather, heat flow to the vein wall and its subsequent temperature increase from two independent heat sources. The first is the exceedingly hot carbonized layer covering the fiber tip; the second is the hot blood surrounding the fiber tip, heated up by direct absorption of the laser light. Both mechanisms are about equally effective for all laser wavelengths. Therefore, our model concurs the finding of Vuylsteke and Mordon (Ann Vasc Surg 26:424-433, 2012) of more circumferential vein wall injury in veins (nearly) devoid of blood, but it does not support their proposed explanation of direct light absorption by the vein wall. Furthermore, EVLA appears to be a more efficient therapy by the combination of higher laser power and faster pullback velocity than by the inverse combination. Our findings suggest that 1,470 nm achieves the highest EVLA efficacy compared to the shorter wavelengths at all vein diameters considered. However, 1,950 nm of EVLA is more efficacious than 1,470 nm albeit only at very small inner vein diameters (smaller than about 1 mm, i.e., veins quite devoid of blood). Our model confirms the efficacy of both clinical procedures at 810 and 1,470 nm. In conclusion, our model simulations suggest that direct light absorption by the vein wall is relatively unimportant, despite being the supposed mechanism of action of EVLA that drove the introduction of new lasers with different wavelengths. Consequently, the presumed advantage of wavelengths targeting water rather than hemoglobin is flawed. Finally, the model predicts that EVLA therapy may be optimized by using 1,470 nm of laser light, emptying of the vein before treatment, and combining a higher laser power with a greater fiber tip pullback velocity.

Endovenous laser ablation (EVLA): a review of mechanisms, modeling outcomes, and issues for debate.

Endovenous laser ablation (EVLA) is a commonly used and very effective minimally invasive therapy to manage leg varicosities. Yet, and despite a clinical history of 16 years, no international consensus on a best treatment protocol has been reached so far. Evidence presented in this paper supports the opinion that insufficient knowledge of the underlying physics amongst frequent users could explain this shortcoming. In this review, we will examine the possible modes of action of EVLA, hoping that better understanding of EVLA-related physics stimulates critical appraisal of claims made concerning the efficacy of EVLA devices, and may advance identifying a best possible treatment protocol. Finally, physical arguments are presented to debate on long-standing, but often unfounded, clinical opinions and habits. This includes issues such as (1) the importance of laser power versus the lack of clinical relevance of laser energy (Joule) as used in Joule per centimeter vein length, i.e., in linear endovenous energy density (LEED), and Joule per square centimeter vein wall area, (2) the predicted effectiveness of a higher power and faster pullback velocity, (3) the irrelevance of whether laser light is absorbed by hemoglobin or water, and (4) the effectiveness of reducing the vein diameter during EVLA therapy.

Asymptomatic Infant Rib Fractures Are Primarily Non-abuse-Related and Should Not Be Used to Assess Physical Child Abuse.

Finding infant rib fractures was for many years an almost undisputed proof that physical child abuse took place. Yet, these rib fractures are virtually always occult and asymptomatic and are only identified when looked for, usually with X-rays, from physical child abuse accusations related to, e.g., suspicion of the shaken baby syndrome. In a recent systematic literature review (searched in Cochran, Embase, PubMed and Sociological Abstracts), Güvensel questioned the diagnostic accuracy of rib fractures to be caused by abuse, due to lack of sufficient scientific evidence. Further, there is currently a world-wide disagreement between physicians considering themselves child abuse specialized, and physicians that explore non-abuse-related symptoms that may mimic physical abuse, which, it is hoped, will significantly reduce current unjustified child abuse diagnoses. In an attempt to help resolving this disagreement, we hypothesize that the probability of physical child abuse-related infant rib fractures is significantly lower than the probability of all other possible non-abuse-related causes of occult asymptomatic infant rib fractures, e.g., from birth trauma, prematurity, osteogenesis imperfecta, hypermobile Ehlers-Danlos Syndrome, severe chronic placental pathology (e.g., massive perivillous fibrin depositions and severe chronic histiocytic intervillositis), and vitamin-D deficiency. As method, we attempted to assess the incidence of these various causes of infant rib fractures, in the Netherlands and the USA. The results are that the estimated Dutch and USA physical abuse-related infant rib fracture incidences are at least about 250 and 45 times lower than the sum of all the non-abuse-related estimates. Because these latter rib fractures are occult and asymptomatic, it is likely that (many) more could be out there. In conclusion, occult asymptomatic rib fractures develop perinatally, virtually always as birth trauma, in infants with sufficiently weak bones due to vitamin D deficiency, transmitted by their vitamin D deficient pregnant mothers. This group also includes cortical rib cracks due to deformation forces, with an estimated 186/100,000 incidence. And, despite obvious uncertainties in all estimated incidences, we provided strong evidence that our hypothesis has relevance, implying that the abundant occult asymptomatic rib fractures, when found in infants, should not be used to assess potential physical child abuse.

Child Abuse, Misdiagnosed by an Expertise Center-Part II-Misuse of Bayes' Theorem.

A newborn girl had, from two weeks on, small bruises on varying body locations, but not on her chest. Her Armenian grandmother easily bruised, too. Her mother was diagnosed with hypermobility-type Ehlers-Danlos-Syndrome (hEDS), an autosomal dominant connective tissue disorder, with a 50% inheritance probability. Referral to a University Medical Center located "Dutch Expertise Center for Child Abuse" resulted (prior to consultation) in physical abuse suspicion. Protocol-based skeletal X-rays showed three healed, asymptomatic rib fractures. A protocol-based Bayesian likelihood ratio guesstimation gave 10-100, erroneously used to suggest a 10-100 times likelier non-accidental-than-accidental cause. Foster care placement followed, even in a secret home, where she also bruised, suggesting hEDS inheritance. Correct non-accidental/accidental Bayes' probability of symptoms is (likelihood ratio) × (physical abuse incidence). From the literature, we derived an infant abuse incidence between about ≈0.0009 and ≈0.0026 and a likelihood ratio of <5 for bruises. For rib fractures, we used a zero likelihood ratio, arguing their cause was birth trauma from the extra delivery pressure on the chest, combined with fragile bones as the daughter of an hEDS-mother. We thus derived a negligible abuse/accidental probability between <5 × 0.0009 <0.005 and <5 × 0.0026 <0.013. The small abuse incidence implies that correctly using Bayes' theorem will also miss true infant physical abuse cases. Curiously, because likelihood ratios assess how more often symptoms develop if abuse did occur versus non-abuse, Bayes' theorem then implies a 100% infant abuse incidence (unwittingly) used by LECK. In conclusion, probabilities should never replace differential diagnostic procedures, the accepted medical method of care. Well-known from literature, supported by the present case, is that (child abuse pediatrics) physicians, child protection workers, and judges were unlikely to understand Bayesian statistics. Its use without statistics consultation should therefore not have occurred. Thus, Bayesian statistics, and certainly (misused) likelihood ratios, should never be applied in cases of physical child abuse suspicion. Finally, parental innocence follows from clarifying what could have caused the girl's bruises (inherited hEDS), and rib fractures (birth trauma from fragile bones).