A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder resulting in progressive muscle weakness. In December 2016, the U.S. Food and Drug Administration approved the first treatment for SMA, a drug named nusinersen (Spinraza) that is administered intrathecally. However many children with SMA have neuromuscular scoliosis or spinal instrumentation resulting in challenging intrathecal access. Therefore alternative routes must be considered in these complex patients. OBJECTIVE: To investigate routes of drug access, we reviewed our institutional experience of administering intrathecal nusinersen in all children with spinal muscular atrophy regardless of spinal anatomy or instrumentation. MATERIALS AND METHODS: We reviewed children with SMA who were referred for intrathecal nusinersen injections from March to December 2017 at our institution. In select children with spinal hardware, spinal imaging was requested to facilitate pre-procedure planning. Standard equipment for intrathecal injections was utilized. All children were followed up by their referring neurologist. RESULTS: A total of 104 intrathecal nusinersen injections were performed in 26 children with 100% technical success. Sixty procedures were performed without pre-procedural imaging and via standard interspinous technique. The remaining 44 procedures were performed in 11 complex (i.e. neuromuscular scoliosis or spinal instrumentation) patients requiring pre-procedural imaging for planning purposes. Nineteen of the 44 complex procedures were performed via standard interspinous technique from L2 to S1. Twenty-two of the 44 complex procedures were performed using a neural-foraminal approach from L3 to L5. Three of the 44 complex procedures were performed via cervical puncture technique. There were no immediate or long-term complications but there was one child with short-term complications of meningismus and back pain at the injection site. CONCLUSION: Although we achieved 100% technical success in intrathecal nusinersen administration, our practices evolved during the course of this study. As a result of our early experience we developed an algorithm to assist in promoting safe and effective nusinersen administration in children with spinal muscular atrophy regardless of SMA type, abnormal spinal anatomy and complex spinal instrumentation.

Safety and effectiveness of percutaneous cholecystostomy in critically ill children who are immune compromised.

BACKGROUND: Acalculous cholecystitis is known to develop in critically ill patients without cystic duct obstruction. In the past, treatment for acalculous cholecystitis has been cholecystectomy; however, many children who are critically ill are Percutaneous cholecystostomy is likely the procedure of choice in this subgroup of patients. OBJECTIVE: To assess the safety and effectiveness of percutaneous cholecystostomy in critically ill and immune-compromised children with acalculous cholecystitis. MATERIALS AND METHODS: Retrospective review of immune-compromised and critically ill children who underwent percutaneous cholecystostomy between 2006 and 2013. Diagnostic imaging performed included ultrasound, CT and hepatobiliary scintigraphy. Every percutaneous cholecystostomy was performed using imaging guidance. RESULTS: Ten critically ill and immune-compromised children with acalculous cholecystitis underwent percutaneous cholecystostomy. Seven boys and 3 girls, ranging in age from 10 months to 15 years 8 months, were treated. Six of the immune-compromised children had received a bone marrow transplant for leukemia (5 children) or severe combined immunodeficiency (SCID) (1 child), and ranged from 18 to 307 days post bone marrow transplant at the time of their percutaneous cholecystostomy. Of the remaining four immune-compromised children with acalculous cholecystitis who underwent percutaneous cholecystostomy, two had leukemia, one had SCID and lymphoma, and the fourth was undergoing treatment for undifferentiated germ cell tumor. The 10 percutaneous gallbladder drains were placed using a transhepatic approach, except one unintentional transperitoneal approach. There were no complications. Three gallbladder drains were removed in Interventional Radiology. Those three patients had a return to normal gallbladder function and didn't require cholecystectomy. Two drains were removed during cholecystectomy and another as an outpatient. Four patients died in the hospital due to multiorgan system failure, with indwelling gallbladder drains. CONCLUSION: Percutaneous cholecystostomy is a safe procedure in immune-compromised and critically ill children with acalculous cholecystitis. Percutaneous cholecystostomy may obviate the need for future cholecystectomy.

Greater saphenous venous access as an alternative in children.

BACKGROUND: In the pediatric population, obtaining venous access in high-risk neonates, severely ill children with cardiac anomalies or very young children (<10 kg) can be very challenging. In the literature to date, the greater saphenous vein has not been primarily used by interventional radiologists as an entry site for venous access in children. OBJECTIVE: To demonstrate the utility and effectiveness of using the greater saphenous vein as a venous access site for the placement of peripherally inserted central catheters in children. MATERIALS AND METHODS: This is a retrospective study from a large tertiary care children's hospital from November 2010 to August 2012. Peripheral insertion of central venous catheters (PICC) using the greater saphenous vein was attempted in 86 children ranging in age from 3 days to 17 years (mean: 1.8 years). Indications included congenital heart disease, urinary tract infection, intravenous access, pneumonia, meningitis, total parenteral nutrition, sepsis and other infections. All procedures were performed by interventional radiologists. No insertion-related complications were identified. There was no follow-up planning, but no mechanical or infectious complications were brought to our attention. RESULTS: Of the 86 patients in whom PICC placement was attempted, placement was successful in 67 (78%). Forty-two PICCs were placed in the greater saphenous vein at the thigh level using US guidance and 25 at the ankle level using anatomical landmarks. The mean weight of the 67 patients who underwent successful placement was 9.98 kg, with 51 (76%) weighing <10 kg. The mean vessel diameter in placement failures was 1.35 mm compared to 1.83 mm in successful placement. Inability to obtain venous access was the cause of failure in all thigh access sites while inability to advance the catheter centrally was the cause of failure for all ankle access sites. A total of 1,060 catheter days (with a maximum dwell time of 97 days in one patient) were reviewed without complication. CONCLUSION: In children, the greater saphenous vein provides a safe, suitable alternative for venous access, particularly in very young children (<10 kg) and in a select group of older children who are not mobile. In the lower extremities, greater saphenous venous puncture and access may be a preferred initial access site in small children to preserve future venous access.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Cytochemical Characterization of Cerebrospinal Fluid Macrophage Inclusions in Pediatric Patients Receiving Intrathecal Nusinersen (SPINRAZA®) for Spinal Muscular Atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by biallelic deletion of the SMN1 gene. Nusinersen, an antisense oligonucleotide delivered intrathecally, binds to the pre-mRNA of SMN1's pseudogene, SMN2, to prevent exon skipping and produce functional SMN protein to compensate for the deficiency caused by SMN1 deletion. CASE PRESENTATION: We reviewed 15 cerebrospinal fluid (CSF) cytology specimens from 8 patients receiving nusinersen for SMA. Macrophages with peculiar inclusions ("nusinophages") were seen in 8 specimens from 4 of the patients: 1 infant and 3 children with SMA type 1. This finding has only previously been reported in adults with SMA types 2 and 3 and in 2 infants with SMA type 1. DISCUSSION/CONCLUSION: Specimens containing nusinophages had a significantly higher proportion of macrophages and lower proportion of lymphocytes than those in which nusinophages were not detected. The macrophage inclusions do not represent iron or microorganisms and instead are composed, at least in part, of glycosaminoglycans. Because CSF is a common specimen type, cytotechnologists and cytopathologists need to be aware of these inclusions, so they do not interpret them erroneously as evidence of infection or hemorrhage, especially in light of the fact that oligonucleotide therapy has been approved for a variety of conditions and is currently under investigation for intrathecal delivery in several other neurodegenerative disorders.

Evaluation of ultrasound-guided radial artery cannulation in children.

OBJECTIVE: To compare ultrasound (US)-guided radial artery cannulation with the traditional palpation technique. DESIGN: : Prospective randomized study. SETTING: Operating room in a tertiary care pediatric center. PATIENTS: One hundred fifty-two children under 18 yrs of age requiring radial artery cannulation. INTERVENTIONS: Patients were randomized to either 1) palpation or 2) US guidance technique for radial artery cannulation. MEASUREMENTS AND MAIN RESULTS: The primary end point of the study was the time taken for attempted cannulation by the first operator at the first site. Secondary end points included the number of attempts at arterial cannulation, the number of cannulae used, and the need for additional assistance from another anesthesiologist. Eighty and 72 children were randomized to the palpation and the US-guided groups, respectively. There were no statistically significant differences in age, gender, weight, and systolic blood pressure between the two study groups. The designated first operator (20 pediatric subspecialty trainees and eight consultant anesthesiologists) had previous experience in US-guided arterial cannulation in <10 cases, with 94% having experience in <5 cases. Although the radial artery was eventually cannulated in all patients, the designated operator was successful at the first site of cannulation in only 66% and 69% in the palpation and US groups, respectively. There were no statistically significant differences between the groups in time to successful cannulation, total number of attempts, number of successful cannulations during the first attempt, or in the number of cannulae used for catheterization. CONCLUSIONS: US guidance did not facilitate faster cannulation of the radial artery in children in our study.

Traumatic lower extremity arteriovenous fistulae in children.

Traumatic arteriovenous fistulae are rare injuries in the pediatric population. Most are caused by penetrating injuries or are post-surgical in nature. Fistulae resulting from non-penetrating injuries are often missed early in the course of physical examination. This occurs due to the absence of clinical signs of arterial or venous injury, despite the close proximity of the affected vessels to point of injury. Likewise, signs and symptoms of post-surgical vascular injury may be difficult to discern from normal postoperative discomfort. The astute clinician must be on alert for unusual presentations of vascular injury to intervene in an expeditious manner. This article presents a series of vascular complications following either blunt injury or surgical management of the lower extremity in children who presented to our facility between November 2004 and December 2005.

CT-guided percutaneous steroid injection for management of inflammatory arthropathy of the temporomandibular joint in children.

OBJECTIVE: The purposes of this study were to retrospectively review an injection technique, to develop a grading system for evaluation of imaging findings, and to report preliminary outcome related to percutaneous CT-guided steroid injection into the temporomandibular joints of children with inflammatory arthropathy. CONCLUSION: CT-guided steroid injection into the temporomandibular joint of children with inflammatory arthropathy results in clinical and imaging improvement in a substantial proportion of children treated.

Validation of the bispectral index monitor for measuring the depth of sedation in children.

The Bispectral Index (BIS) is an empirically calibrated number derived from adult electroencephalograph data that correlates with the depth of sedation in adults. We tested the hypothesis that the BIS score is a valid measure of the depth of pediatric sedation in a study designed to avoid limitations of a previously published report. BIS values from 96 healthy ASA physical status I-II children aged 1-12 yr undergoing sedation were continually recorded and electronically transferred to a computer. Two independent observers blinded as to BIS score evaluated sedation using the Observer's Assessment of Alertness/Sedation (OAA/S) and the University of Michigan Sedation Scale (UMSS) at 3-5 min intervals. There was a significant correlation between BIS and UMSS and between BIS and OAA/S by both the Spearman's rank correlation test and by prediction probability (P < 0.001). In children <6 yr, there was a significant correlation between BIS and the clinical sedation scores for subgroups undergoing invasive and noninvasive procedures (P < 0.001). There was also good agreement between the 2 independent observers who assessed clinical sedation scores (kappa = 0.51, P < 0.001). We conclude that the BIS monitor is a quantitative, nondisruptive and easy to use depth of sedation monitor in children.

Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation.

Infants with congenital hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (K(ATP)) genes, SUR1 and K(ir)6.2, cause diffuse hyperinsulinism. K(ATP) channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); K(ATP) channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. These results indicate that preoperative AIR tests do not distinguish focal vs. diffuse disease because some K(ATP) channel mutations retain responsiveness to tolbutamide. The ASVS test can be used to localize focal lesions in infants. The combination of ASVS, careful intraoperative histologic analysis, and surgical expertise succeeded in correcting hypoglycemia in 86% of the infants with focal hyperinsulinism.

Priapism in children: treatment with embolotherapy.

BACKGROUND: Priapism is defined as involuntary, prolonged penile erection caused by factors other than sexual arousal, and is classified as either low-flow or high-flow. Embolotherapy is an accepted form of therapy in adults with high-flow priapism. Because the differences in etiology, management and outcome are significant, accurate and timely diagnosis is imperative. OBJECTIVE: The purpose of this report is to present our experience with embolotherapy for treatment of high-flow priapism in three children. PATIENTS AND METHODS: This was a retrospective study. During an 18-month period, three boys ranging in age from 6 to 15 years presented with priapism. All three children were treated with embolotherapy. RESULTS: All three children were successfully treated with angiography and embolotherapy. One boy had a presentation that initially raised the possibility of low-flow priapism. No complications occurred, and to date all children are able to maintain normal erections. CONCLUSION: Subselective transcatheter embolization is the procedure of choice for high-flow priapism. In cases where priapism persists despite adequate therapy, angiography might be useful to exclude high-flow disease. In children with high-flow priapism, selective occlusion of the penile arteriovenous fistula led to detumescence and normal erectile function.

Benefit of fluoroscopically guided intraarticular, long-acting corticosteroid injection for subtalar arthritis in juvenile idiopathic arthritis.

BACKGROUND: Children with arthritis may endure a lifetime of disfigurement, dysfunction, and pain if acute inflammation progresses to chronic changes in the joint cartilage and underlying bone. Intraarticular steroids have become an integral component of treatment, but at times are difficult to deliver to joints, such as the subtalar joint, that have complex anatomies. OBJECTIVE: We describe our technique and outcomes using fluoroscopically guided intraarticular subtalar steroid injection in patients with active symptoms of juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: Fluoroscopically guided subtalar joint injections were performed in 38 children (mean age 6.7 years). Medical records were reviewed retrospectively and improvement was evaluated clinically by the degree of foot movement in eversion and inversion. RESULTS: Subtalar joint injection was technically successful in 100% of the JIA patients with improvement in physical symptoms in 34/38 (89%). Of the 38 children, 32 were followed up within 13 weeks of the initial injection and, therefore, satisfied the eligibility criteria for resolution of arthritis. Of these 32 children, 14 showed clinical resolution (44%). The mean duration of improvement was 1.2 +/- 0.9 years. Children with a longer interval (>1 year) from diagnosis to treatment had significantly less resolution (P = 0.04). Local subcutaneous atrophy or hypopigmentation were observed in 53% of the children after steroid injection (20/38). These minor complications were associated with a greater volume of steroid injected into the site per child (P = 0.02). CONCLUSION: Fluoroscopically guided subtalar joint injection is an effective treatment for subtalar arthropathy. Prompt referral for intraarticular steroid treatment in the acute phase improves response. Skin changes often occur at the injection site, and specific precautions should be employed to reduce this risk. Prospective study is indicated to determine the most effective treatment strategy to prevent long-term pain and disability.

Benefit of intraarticular corticosteroid injection under fluoroscopic guidance for subtalar arthritis in juvenile idiopathic arthritis.

OBJECTIVE: To determine the demographics of subtalar arthritis, the response to intraarticular corticosteroid injection, and the injection complication rate in a clinic sample of children with juvenile idiopathic arthritis (JIA). METHODS: A chart review was performed of all patients at a tertiary medical center who underwent subtalar corticosteroid injection during the past 5 years. Injection of 1 ml of triamcinolone hexacetonide or acetonide into the midsubtalar joint was performed using a lateral oblique approach under fluoroscopic guidance. Improvement was defined by enhanced foot inversion and eversion at the following office visit. RESULTS: Thirty-eight patients underwent 55 subtalar injections during the study period. All 7 JIA subtypes were represented. Thirty-one patients (82%) had subtalar arthritis at time of JIA diagnosis and 32 (84%) had concomitant tibiotalar ankle arthritis. Improvement was observed following 34 (89%) of the initial 38 injections. The mean duration of improvement was 1.2 years (SD +/- 0.9). Twenty patients (53%) developed hypopigmentation or subcutaneous atrophy. This complication was associated with a higher volume of injected corticosteroid per patient weight (p = 0.02) and with less efficacious injections (p = 0.04). CONCLUSION: Subtalar arthritis in children with JIA is common. Similar to other joints, subtalar arthritis responds to corticosteroid injection in approximately 90% of cases and often remains improved for greater than one year. Hypopigmentation and subcutaneous atrophy are frequent complications and are likely related to the dose of injected corticosteroid and possibly the accuracy of needle placement.

Interventional radiology: a modular approach.

The authors offer a modular approach to the development of new procedures in the field of pediatric interventional radiology as a conceptual model and a springboard for further discussion.

Botulinum toxin type a injections to salivary glands: combination with single event multilevel chemoneurolysis in 2 children with severe spastic quadriplegic cerebral palsy.

We describe 2 children with severe spastic quadriplegic cerebral palsy (CP) who have significant drooling and frequent aspiration pneumonia. They underwent simultaneous botulinum toxin type A (BTX-A) injections to salivary glands for drooling and prevention of aspiration pneumonia along with single-event multilevel chemoneurolysis (SEMLC) with BTX-A and 5% phenol for severe diffuse spasticity. There was significant improvement in drooling, frequency of aspiration pneumonia, and spasticity without adverse effect. BTX-A injections into the salivary glands, in addition to SEMLC, for these 2 children with medically complicated severe spastic quadriplegic CP, were safe and highly successful procedures, which improved their health-related quality of life.

May-Thurner syndrome (iliac vein compression) and thrombosis in adolescents.

May-Thurner syndrome refers to anatomic compression of the left iliofemoral vein by the overriding right iliac artery. We report three adolescents who presented to our pediatric hospital with iliac vein thrombosis and were diagnosed with May-Thurner syndrome. Each received catheter-directed thrombolysis followed by balloon angioplasty to restore flow. Two patients had endovascular stents placed. The procedures were well tolerated, without major complications. Additional thrombophilic risk factors were identified in each patient. Though uncommon, pediatric hematologists should consider May-Thurner syndrome in adolescents who present with a left lower extremity thrombosis. Aggressive therapy may be warranted due to the risk of post-thrombotic syndrome.

Gastrostomy tubes: facts, fallacies, fistulas, and false tracts.

The first successful gastrostomy was performed 130 years ago. Although it is difficult to ascertain the exact number of gastrostomy or jejunostomy tubes placed annually in the United States, it is estimated approximately 230,000 gastrostomy procedures were performed in U.S. hospitals in 2001. Of these, 11,000 were performed in children. Despite the many years gastrostomy tubes have been in use, they are not free from complications. The purpose of this article is to review the authors' experience with pediatric patients who have undergone radiographic placement of gastrostomy or jejunostomy tubes.