Surface Reconstruction of the Pediatric Larynx via Structure from Motion Photogrammetry: A Pilot Study.

Endoscopy is the gold standard for characterizing pediatric airway disorders, however, it is limited for quantitative analysis due to lack of three-dimensional (3D) vision and poor stereotactic depth perception. We utilize structure from motion (SfM) photogrammetry, to reconstruct 3D surfaces of pathologic and healthy pediatric larynges from monocular two-dimensional (2D) endoscopy. Models of pediatric subglottic stenosis were 3D printed and airway endoscopies were simulated. 3D surfaces were successfully reconstructed from endoscopic videos of all models using an SfM analysis toolkit. Average subglottic surface error between SfM reconstructed surfaces and 3D printed models was 0.65 mm as measured by Modified Hausdorff Distance. Average volumetric similarity between SfM surfaces and printed models was 0.82 as measured by Jaccard Index. SfM can be used to accurately reconstruct 3D surface renderings of the larynx from 2D endoscopy video. This technique has immense potential for use in quantitative analysis of airway geometry and virtual surgical planning.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia.

BACKGROUND: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. METHODS: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. RESULTS: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. CONCLUSIONS: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Virtually Assisted Personalized Tracheostomy Tube Design in Pediatric Complex Airway Anomalies.

We sought to assess the feasibility of virtually assisted personalized tracheostomy tube (vapTT) implementation for patients with congenital airway anomalies (CAAs) and persistent tracheostomy tube (TT)-related respiratory failure at a tertiary pediatric hospital. Three patients (0-18 years) with CAAs and recurrent TT-related respiratory complications were managed with vapTT over 5 years. Patients underwent airway computed tomography acquisition with 3-dimensional reconstruction and TT virtual modeling for shape customization. Models were transferred to Bivona for fabrication based on industry-standard materials and processes. Clinical information and tracheoscopies assessing position, obstruction, and granulation were reviewed. Patients demonstrated resolution of visualized TT-related obstruction, granulation, or ulceration and de-escalation of respiratory support. Clinical events requiring urgent tracheoscopy decreased in all 3 patients. Sufficient relief of critical airway obstruction allowed progression of medical care and/or discharge. VapTTs are feasible for patients with CAA. This new frontier in personalized devices may serve uniquely challenging patient populations for whom standard treatments have failed.

Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth.

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are treatment challenges. Traditionally, these conditions require multiple invasive interventions, with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating lipomatosis (FIL). We describe prospective treatment of 5 children with PIK3CA-associated HNLMs or head and neck FIL with alpelisib monotherapy. METHODS: A total of 5 children with PIK3CA-associated HNLMs (n = 4) or FIL (n = 1) received alpelisib monotherapy (aged 2-12 years). Treatment response was determined by parental report, clinical evaluation, diary/questionnaire, and standardized clinical photography, measuring facial volume through 3-dimensional photos and magnetic resonance imaging. RESULTS: All participants had reduction in the size of lesion, and all had improvement or resolution of malformation inflammation/pain/bleeding. Common invasive therapy was avoided (ie, tracheotomy). After 6 or more months of alpelisib therapy, facial volume was reduced (range 1%-20%) and magnetic resonance imaging anomaly volume (range 0%-23%) were reduced, and there was improvement in swallowing, upper airway patency, and speech clarity. CONCLUSION: Individuals with head and neck PROS treated with alpelisib had decreased malformation size and locoregional overgrowth, improved function and symptoms, and fewer invasive procedures.

Comparison of Slide Tracheoplasty Technique on Postoperative Anatomic Outcomes in Three-Dimensional Printed Models.

OBJECTIVES/HYPOTHESIS: We hypothesized that the use of three-dimensional (3D) printed tracheal models to reproducibly simulate surgical technique variations in slide tracheoplasty would demonstrate the quantitative impact of surgical variables on postoperative tracheal dimensions. STUDY DESIGN: Prospective analysis of three-dimensional printed surgical simulation models. METHODS: Slide tracheoplasty was performed on 3D printed long segment tracheal stenosis models with combinations of tracheal transection incision angle (90°, 45° beveled superior to inferior, 45° beveled inferior to superior) and tracheal transection location relative to the stenosis (at midpoint, 2 mm each superior and inferior to midpoint). Postoperative computed tomography (CT) scans measured changes in tracheal length, volume, and cross-sectional area compared to controls. Statistical analysis was performed using one-way analysis of variance and unpaired two-tailed t-tests. RESULTS: Slide tracheoplasty yielded 27 reconstructed tracheas. On average, slide tracheoplasty reduced total tracheal length by 36%. Beveled tracheal incisions yielded 9.5% longer final tracheas than straight transection incisions (P < .0001). Cross-sectional area at the stenosis midpoint increased from 9.0 mm2 to 45 mm2 but did not vary with technique (P > .05). Total tracheal luminal volume increased from 900 mm3 to 1378 mm3 overall and was largest with beveled incisions (P = .03). More material was discarded with straight incisions compared to beveled (89 mg vs. 19 mg, P < .0001). CONCLUSIONS: Beveled tracheal transection incisions resulted in increased tracheal length, longer anastomotic segments, increased volume, and reduced tissue waste as compared to straight incisions. Offsetting the incision from the midpoint of stenosis did not significantly affect reconstructed tracheal morphology. Using 3D printed models for surgical simulation can be helpful for the quantitative study of the effect isolated surgical variables on technical outcomes. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1306-1312, 2022.

Accuracy and Reliability of 4D-CT and Flexible Laryngoscopy in Upper Airway Evaluation in Robin Sequence.

OBJECTIVES: To evaluate the performance of 4-dimensional computed tomography (4D-CT) in assessing upper airway obstruction (UAO) in patients with Robin sequence (RS) and compare the accuracy and reliability of 4D-CT and flexible fiber-optic laryngoscopy (FFL). STUDY DESIGN: Prospective survey of retrospective clinical data. SETTING: Single, tertiary care pediatric hospital. METHODS: At initial and 30-day time points, a multidisciplinary group of 11 clinicians who treat RS rated UAO severity in 32 sets of 4D-CT visualizations and FFL videos (dynamic modalities) and static CT images. Raters assessed UAO at the velopharynx and oropharynx (1 = none to 5 = complete) and noted confidence levels of each rating. Intraclass correlation and Krippendorff alpha were used to assess intra- and interrater reliability, respectively. Accuracy was assessed by comparing clinician ratings with quantitative percentage constriction (QPC) ratings, calculated based on 4D-CT airway cross-sectional area. Results were compared using Wilcoxon rank-sum and signed-rank tests. RESULTS: There was similar intrarater agreement (moderate to substantial) with 4D-CT and FFL, and both demonstrated fair interrater agreement. Both modalities underestimated UAO severity, although 4D-CT ratings were significantly more accurate, as determined by QPC similarity, than FFL (-1.06 and -1.46 vs QPC ratings, P = .004). Overall confidence levels were similar for 4D-CT and FFL, but other specialists were significantly less confident in FFL ratings than were otolaryngologists (2.25 and 3.92, P < .0001). CONCLUSION: Although 4D-CT may be more accurate in assessing the degree of UAO in patients with RS, 4D-CT and FFL assessments demonstrate similar reliability. Additionally, 4D-CT may be interpreted with greater confidence by nonotolaryngologists who care for these patients.

4D Computed Tomography for Dynamic Upper Airway Evaluation in Robin Sequence.

Thorough assessment of dynamic upper airway obstruction (UAO) in Robin sequence (RS) is critical, but traditional evaluation modalities have significant limitations. Four-dimensional computed tomography (4D-CT) is promising in that it enables objective and quantitative evaluation throughout all phases of respiration. However, there exist few protocols or analysis tools to assist in obtaining and interpreting the vast amounts of obtained data. A protocol and set of data analysis tools were developed to enable quantification and visualization of dynamic 4D-CT data. This methodology was applied to a sample case at 2 time points. In the patient with RS, overall increases in normalized airway caliber were observed from 5 weeks to 1 year. There was, however, continued dynamic obstruction at all airway levels, though objective measures of UAO did improve at the nasopharynx and oropharynx. Use of 4D-CT and novel analyses provide additional quantitative information to evaluate UAO in patients with RS.

Reliability of Measuring Insertion Depth in Cochlear Implanted Infants and Children Using Cochlear View Radiography.

OBJECTIVES: Cochlear implant depth of insertion affects audiologic outcomes and can be measured in adults using plain films obtained in the "cochlear view." The objective of this study was to assess interrater and intrarater reliability of measuring depth of insertion using cochlear view radiography. STUDY DESIGN: Prospective, observational. SETTING: Tertiary referral pediatric hospital. SUBJECTS AND METHODS: Patients aged 11 months to 20 years (median, 4 years; interquartile range [IQR], 1-8 years) undergoing cochlear implantation at our institution were studied over 1 year. Children underwent cochlear view imaging on postoperative day 1. Films were deidentified and 1 image per ear was selected. Two cochlear implant surgeons and 2 radiologists evaluated each image and determined angular depth of insertion. Images were re-reviewed 6 weeks later by all raters. Inter- and intrarater reliability were calculated with intraclass correlation coefficients (ICCs). RESULTS: Fifty-seven ears were imaged from 42 children. Forty-nine ears (86%) had successful cochlear view x-rays. Median angular depth of insertion was 381° (minimum, 272°; maximum, 450°; IQR, 360°-395°) during the first round of measurement. Measurements of the same images reviewed 6 weeks later showed median depth of insertion of 382° (minimum, 272°; maximum, 449°; IQR, 360°-397°). Interrater and intrarater reliability ICCs ranged between 0.81 and 0.96, indicating excellent reliability. CONCLUSIONS: Postoperative cochlear view radiography is a reliable tool for measurement of cochlear implant depth of insertion in infants and children. Further studies are needed to determine reliability of intraoperatively obtained cochlear view radiographs in this population.

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies.

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.

Pressure gradients, laboratory changes, and outcomes with transjugular intrahepatic portosystemic shunts in pediatric portal hypertension.

INTRODUCTION: Indications for TIPS are well described in adults and involve complications of PHTN. Complications from PHTN are associated with PSG of > 12 mm Hg in adults. It is unclear if these parameters apply to children with PHTN. OBJECTIVE: To assess whether adult criteria for TIPS placement can be utilized in children, describe laboratory changes over time, and report outcomes. METHODS: We performed a retrospective review of 34 pediatric patients who underwent TIPS, examining indications, radiology, PSG reductions, laboratory changes, and outcomes. RESULTS: Most patients had PHTN due to parenchymal liver disease including congenital hepatic fibrosis (n = 5), biliary atresia (n = 5), cystic fibrosis-related liver disease (n = 3) and cavernous transformation of the portal vein (n = 6). Indications for TIPS included variceal bleeding, recurrent ascites, and maintenance of portal vein flow following thrombolysis. Variceal bleeding was observed in six children with PSG < 12 mm Hg. Minor complications occurred in eight subjects. Continued bleeding occurred in one patient. Six patients were successfully bridged to transplantation, and three patients died secondary to end-stage disease. Standard laboratory tests stabilized after TIPS placement and hematocrit increased. CONCLUSION: TIPS placement in pediatric patients was performed for complications of PHTN. Unlike adult series, a substantial proportion of our cases treated extrahepatic PHTN from cavernous transformation of the portal vein. Children presented with sequelae of PHTN with PSG below 12 mm Hg, below the adult standard. We found TIPS in pediatrics to be safe and effective with laboratory stabilization and improvement in hematocrit.

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD.

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.

Simulation-Guided Tracheotomy in a Patient With Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare disorder that causes heterotopic bone formation leading to chest wall and spinal deformities. This case describes an 11-year-old female with FOP who presented in respiratory failure necessitating two emergent fiberoptic nasotracheal intubations. The patient had severe trismus, rotary flexion of the neck, and distortion of the airway. A three-dimensional printed model based off of a computed tomography reconstruction was created for an in situ simulation before the true procedure. The surgery and trach change were both uneventful. We propose that with careful preoperative planning, tracheotomy can be an appropriate option for FOP patients. Laryngoscope, 129:812-817, 2019.

Prevalence of Abnormal Magnetic Resonance Imaging Findings in Children with Persistent Symptoms after Pediatric Sports-Related Concussion.

A subset of patients experience persistent symptoms after pediatric concussion, and magnetic resonance imaging (MRI) is commonly used to evaluate for pathology. The utility of this practice is unclear. We conducted a retrospective cohort study to describe the MRI findings in children with concussion. A registry of all patients seen at our institution from January 2010 through March 2016 with pediatric sports-related concussion was cross-referenced with a database of radiographical studies. Radiology reports were reviewed for abnormal findings. Patients with abnormal computed tomographies or MRI scans ordered for reasons other than concussion were excluded. Among 3338 children identified with concussion, 427 underwent MRI. Only 2 (0.5%) had findings compatible with traumatic injury, consisting in both of microhemorrhage. Sixty-one patients (14.3%) had abnormal findings unrelated to trauma, including 24 nonspecific T2 changes, 15 pineal cysts, eight Chiari I malformations, and five arachnoid cysts. One child underwent craniotomy for a cerebellar hemangioblastoma after presenting with ataxia; another had cortical dysplasia resected after seizure. The 2 patients with microhemorrhage each had three previous concussions, significantly more than patients whose scans were normal (median, 1) or abnormal without injury (median, 1.5; p = 0.048). MRI rarely revealed intracranial injuries in children post-concussion, and the clinical relevance of these uncommon findings remains unclear. Abnormalities unrelated to trauma are usually benign. However, MRI should be thoughtfully considered in children who present with concerning or atypical symptoms.

Spine Computed Tomography Radiation Dose Reduction: Protocol Refinement Based on Measurement Variation at Simulated Lower Radiation Acquisitions.

STUDY DESIGN: Retrospective dose-simulation comparison. OBJECTIVE: To determine if sufficient detail for preoperative analysis of bony anatomy can be acquired at substantially lower doses than those typically used. SUMMARY OF BACKGROUND DATA: Computed tomography (CT) is a preoperative planning tool for spinal surgery. The pediatric population is at risk to express the harmful effects of ionizing radiation. Preoperative CT scans are presently performed at standard pediatric radiation doses not tailored for surgical planning. METHODS: We used the validated GE Noise Injection software to retrospectively modify existing spine and chest CT scans from 10 patients to create CT images that simulated a standard dose (100%), 50% dose, and 25% dose scans. 4 orthopedic surgeons and a pediatric radiologist, blinded to dose, measured minimum medial-lateral pedicle width and maximum anterior-posterior bony length along the axis of presumed pedicle screw placement. A total of 90 axial images were generated to create our sample set. Measurements were evaluated for accuracy, precision, and consistency. RESULTS: For any given rater, there was no clinically relevant difference between measurements at the different dose levels and no apparent degradation in precision at the different dose levels. Consistent variation was observed between raters, the likely result of individual differences in measurement approach. CONCLUSION: Spinal CT scans done for preoperative planning can be performed at 25% of current radiation doses without a loss in surgical planning measurement accuracy or precision. These 25% dose-reduced scans would have average Computed Tomography Dose Index volume dose levels of roughly 1.0 to 2.5 mGy (depending on patient size) and size-specific dose estimates of roughly 2.5 mGy representing a substantial dose savings compared to current practice for many sites. Standardization of consistent landmarks may be useful to further improve inter-rater concordance.

Voiding cystourethrography revisited: descriptive statistics for the detection of vesicoureteral reflux.

OBJECTIVE: To determine which factors might influence the detection of vesicoureteral reflux (VUR), we retrospectively reviewed factors including fluoroscopy time, number of true radiographic acquisitions, and patient characteristics from a large number of voiding cystourethrography (VCUG) examinations. MATERIALS AND METHODS: Nine hundred eighty-seven VCUG examinations performed between March 2006 and March 2009 were randomly selected for review. Data recorded were presence of VUR, patient age and sex, examination indication, follow-up status, presence of a diagnostic radiology trainee, fluoroscopy time, and number of true radiographic acquisitions. For initial examinations, descriptive comparison and logistic analyses were performed. To evaluate which variables related to reflux identification, we analyzed variables by logistic regression after stratifying by patient age (≤ 1 or > 1 year) for both the full sample and cases grouped by VUR severity (grades I and II [mild] or grades III-V [moderate to severe]). RESULTS: Nine hundred eighty-seven VCUG examinations were evaluated for the study (65.5% female; mean age, 3 years 2 months; age range, 2 weeks-16 years), and 761 cases met the inclusion criteria. VUR was detected in 101 of 349 infants (40 mild, 61 moderate to severe) and in 107 of 412 children older than 1 year (52 mild, 55 moderate to severe). A wide range of fluoroscopy times was similar between both positive and negative cases (0.033-4.233 minutes). The number of true radiographic acquisitions differed significantly between the negative and positive cases. CONCLUSION: Descriptive statistics and logistic regression analyses for a large number of VCUG examinations in a pediatric population are summarized. Our results showed that high fluoroscopy times were not associated with a higher likelihood of VUR. There may be a small benefit to the use of true radiographic acquisitions for detecting VUR.

Liver and heart MR relaxometry in iron loading: reproducibility of three methods.

PURPOSE: To compare the derived T2* values and reproducibility of three methods used to assess iron-loading in heart and liver. MATERIALS AND METHODS: In 23 pediatric patients, liver and cardiac gradient-echo imaging datasets (within-exam repeated sequence pairs) were evaluated. Data analyses compared derived relaxation values (average of pairs) and coefficient of variation (reproducibility of pairs). RESULTS: T2* values showed differences across methods, with pixel-wise mean > average fit > pixel-wise median. Coefficient of variation was found to be lower (better) with pixel-wise median and average fit methods compared to the pixel-wise mean technique. Maximum coefficient of variation values were lowest for the pixel-wise median approach in both the heart and liver. CONCLUSION: Differences in derived T2* values between methods must be considered when comparing values to established magnetic resonance imaging (MRI)-biopsy formulas. The pixel-wise median and average fit methods demonstrate substantial benefits in reproducibility compared to the pixel-wise mean method. Since minimal variation in measurement is critical for patient care, median processing of relaxometry data may be preferable in both tissue types.

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

Limitations of using logarithmic transformation and linear fitting to estimate relaxation rates in iron-loaded liver.

BACKGROUND: MRI is being increasingly used to evaluate tissue relaxation in the setting of iron overload. Diagnostic accuracy is strongly dependent upon the acquisition and analysis methods employed. Typically, a multi-echo train of relaxation data is acquired, the resulting curve is fit using a non-linear (exponential) function, and the derived relaxation time is converted to iron concentration by a calibration formula derived from paired MRI-biopsy samples. A theoretically valid processing alternative is to fit a straight line to the relaxation data after logarithmic transformation (log-linear). This log-linear method is more computationally efficient, allowing a full relaxation map to be generated in near real time. This method is present on all scanner platforms and has been published for use in assessing iron concentration. These factors imply methodological validity. OBJECTIVE: To use in vivo and simulation data to show that log-linear fitting can generate highly erroneous relaxation results in iron-loaded tissues. MATERIALS AND METHODS: After IRB approval, exponential and linear fitting were compared in a cohort of 20 patients being evaluated for hepatic iron overload. Simulation analyses were performed to characterize the main factors impacting derived results. RESULTS: In human subjects, log-linear analyses demonstrated gross deviation from exponential results at a moderate relaxation shortening (T2* ~5 ms). Simulation analyses demonstrated that the discrepancy was caused by noise effects and additional signal components violating mono-exponential function shape. CONCLUSION: Log-linear processing results in increasingly erroneous estimation of T2* with iron-loading. Therefore, this method should not be employed for measurement of relaxation behavior in clinical samples.

The use of neuroimaging in the diagnosis of mitochondrial disease.

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

Quantitative in vivo magnetic resonance spectroscopy using synthetic signal injection.

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.