Twin-to-Twin Transfusion Syndrome scenarios - the making of a decision

Thesis (M.A.)--Boston UniversityIntroduction: Twin-to-Twin Transfusion Syndrome (TTTS) is a prenatal condition affecting 10-20% of monochorionic – diamniotic (identical) twins and is defined by unbalanced blood flow from one twin to the co-twin. TTTS is staged using the Quintero Staging System (I-V) based on ultrasound and Doppler findings. Even with the staging, TTTS does not have a linear course of progression and lacks predictably in the outcome of the pregnancy. If it does progress and is left untreated, TTTS has a 100% mortality of both twins. There are various treatments for TTTS including septostomy and serial amnioreductions, but the optimal treatment for TTTS is laser ablation of the communicating placental vessels between both twins. These anastomoses are the pathophysiological cause of the syndrome and LASER treatment allows the twins to recover in utero. LASER treatment is associated with risks, including preterm rupture of membranes and preterm labor in 4% of pregnancies and short-and long-term morbidities in 13% of the twin, with the main cause of all morbidity in TTTS infants being prematurity. Twin-to-Twin Transfusion Syndrome’s associated unpredictability, lack of linear progression, and various risks and outcomes cause decision-making in TTTS to be problematic for both physicians and parents. Methods: A six-month observational period from July 2012 through January 2013, a cohort of women pregnant with monochorionic – diamniotic twins were referred to the Fetal Treatment Program of New England for assessment of TTTS in their twins by ultrasonography. If diagnosed with TTTS, the twins were staged (I-IV) and treatment recommendations were discussed. At Stage I, patients were recommended for observational, conservative management of weekly ultrasounds. If the patient's ultrasound findings were consistent with Stage II, III, or IV, they underwent LASER treatment. During LASER treatment, communicating anastomoses between both twins were ablated using a diode laser. The women were discharged 2 days post-op and were recommended to have at least weekly ultrasounds for the first two weeks after surgery and then every other week ultrasounds thereafter, to monitor each twin’s health. [TRUNCATED

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

International audienceBACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills. RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.