Patient headache questionnaires can improve headache diagnosis and treatment in children.

OBJECTIVE: To examine trends in diagnosis of headache and migraine in a large pediatric neurology cohort, and test whether an electronic health record (EHR)-integrated headache questionnaire can increase specificity of diagnosis and likelihood of prescribing migraine treatment. BACKGROUND: Under-diagnosis of migraine contributes to the burden of disease. As we founded our Pediatric Headache Program in 2013, we recognized that the proportion of patients with headache who were given a diagnosis of migraine was much lower than expected. METHODS: We developed a patient headache questionnaire, initially on paper (2013-2014), then in an electronic database (2014-2016), and finally integrated into our electronic health record (pilot: 2016, full: May 2017). We compared diagnoses and prescribed treatments for new patients who were given a headache diagnosis, looking at trends in the proportion of patients given specific diagnoses (migraine, etc.) versus the non-specific diagnosis, "headache." Next, we conducted a prospective cohort study to test for association between provider use of the form and the presence of a specific diagnosis, then for an association between specific diagnosis and prescription of migraine treatment. RESULTS: Between July 2011 and December 2022 the proportion of new headache patients who were given a diagnosis of migraine increased 9.7% and non-specific headache diagnoses decreased 21.0%. In the EHR cohort (June 2017-December 2022, n = 15,122), use of the provider form increased the rate of specific diagnosis to 87.2% (1839/2109) compared to 75.5% (5708/7560) without a patient questionnaire, nearly doubling the odds of making a specific diagnosis (odds ratio [OR] 1.90, 95% confidence interval [CI]: 1.65-2.19). Compared to those given only a non-specific headache diagnosis who were prescribed a migraine therapy 53.7% (1766/3286) of the time, 75.3% (8914/11836) of those given a specific diagnosis received a migraine therapy, more than doubling the odds of prescription (OR 2.39, 95% CI: 2.20-2.60). CONCLUSIONS: Interventions to improve specificity of diagnosis were effective and led to increased rates of prescription of migraine treatments. These results have been sustained over several years. This headache questionnaire was adapted into the Foundation system of EpicCare, so it is broadly available as a clinical and research tool for institutions that use this EHR software.

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease-modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy, delivers functional human SMN through a one-time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient-centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient-centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti-adeno-associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day-to-day care at time of treatment and patient- and family-centered discussions on realistic expectations are also recommended. We detail the importance of following standard-of-care guidance and long-term monitoring of all children with SMA who have received one or more disease-modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder.

Clinical Experience With Gene Therapy in Older Patients With Spinal Muscular Atrophy.

BACKGROUND: Onasemnogene abeparvovec was recently approved for the treatment of spinal muscular atrophy (SMA) in children younger than two years; however, clinical trials were primarily completed in children younger than seven months, so practical experience dosing older children began in summer 2019. Here, we look at the safety and efficacy of onasemnogene in seven infants older than seven months who were treated at our center. METHODS: Seven patients were included. RESULTS: Acute viral symptoms with emesis and/or fever were seen in six of seven patients two to three days after the infusion. Thrombocytopenia occurred in four of seven patients, and six of seven patients had prolonged steroid courses due to persistently elevated liver enzymes, one of whom required escalation to intravenous steroids. All patients demonstrated motor improvements, which were apparent by three months, although with continued progress in those patients followed for longer periods of time. CONCLUSIONS: Overall, onasemnogene appears to be efficacious in children older than seven months and well tolerated. Side effects were similar to those previously reported, although more common and in some cases more severe and more prolonged than seen in the original trials. The impact of age, weight, and other confounding factors on development of side effects still needs to be elucidated.

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study.

OBJECTIVE: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA). METHODS: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy. RESULTS: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes. CONCLUSIONS: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

Clinical Course in a Patient With Spinal Muscular Atrophy Type 0 Treated With Nusinersen and Onasemnogene Abeparvovec.

Spinal muscular atrophy type 0 is the most severe phenotype of the disease, with patients presenting with contractures, weakness, and respiratory failure at birth, and is typically fatal within weeks. We describe the case of a patient with spinal muscular atrophy type 0 who was treated with both nusinersen and onasemnogene abeparvovec. She has made modest motor improvements since treatment initiation with a 30-point improvement in CHOP-INTEND score, and continues to make motor gains at age 13 months without regression of function, although she remains profoundly weak. Although she has had motor improvements, she has also had continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash. This case highlights the challenges in treating those with more severe disease phenotypes and raises questions of how some systemic complications may respond to current SMN replacement therapies.

A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy.

BACKGROUND: In December 2016, nusinersen gained FDA approval as the first pharmacologic treatment for spinal muscular atrophy (SMA), a disorder of motor neurons and the leading genetic cause of infant mortality. Nusinersen's intrathecal delivery requirement, strict dosage protocol, and accelerated FDA approval presented a challenge to health care centers hoping to implement treatment of patients with SMA. Scheduling logistics, combined with the specific ventilatory, anesthetic, and spinal access needs of this patient population, requires extensive coordination of care. This complexity, in addition to the high cost of treatment, may lead to overburdening of an institution's dosing resources, causing delays in treatment initiation and limiting patients' access to therapy and may result in barriers to coverage. METHODS: We initiated a comprehensive stepwise protocol to maximize patient inclusion, as well as safety and efficiency outcome measures. This retrospective cohort study reviews the dosing process. RESULTS: As a result of immense collaborative efforts involving care coordination of patients and families, in addition to health providers in the divisions of neurology, anesthesiology, pulmonology, orthopedics, interventional radiology, physical therapy, and neurosurgery, we have successfully dosed 62 SMA patients. Throughout this process, we have improved anesthetic techniques, as well as minimized procedural complications and missed scheduled doses. CONCLUSION: We present here recommendations for safe and effective implementation of nusinersen utilizing a multidisciplinary approach, based on our 1 and a half year experience at a tertiary care children's hospital.

Developmental and comparative aspects of posterior medial thalamocortical innervation of the barrel cortex in mice and rats.

The thalamocortical projection to the rodent barrel cortex consists of inputs from the ventral posterior medial (VPM) and posterior medial (POm) nuclei that terminate in largely nonoverlapping territories in and outside of layer IV. This projection in both rats and mice has been used extensively to study development and plasticity of highly organized synaptic circuits. Whereas the VPM pathway has been well characterized in both rats and mice, organization of the POm pathway has only been described in rats, and no studies have focused exclusively on the development of the POm projection. Here, using transport of Phaseolus vulgaris leucoagglutinin(PHA-L) or carbocyanine dyes, we characterize the POm thalamocortical innervation of adult mouse barrel cortex and describe its early postnatal development in both mice and rats. In adult mice, POm inputs form a dense plexus in layer Va that extends uniformly underneath layer IV barrels and septa. Innervation of layer IV is very sparse; a clear septal innervation pattern is evident only at the layer IV/Va border. This pattern differs subtly from that described previously in rats. Developmentally, in both species, POm axons are present in barrel cortex at birth. In mice, they occupy layer IV as it differentiates, whereas in rats, POm axons do not enter layer IV until 1-2 days after its emergence from the cortical plate. In both species, arbors undergo progressive and directed growth. However, no layer IV septal innervation pattern emerges until several days after the cytoarchitectonic appearance of barrels and well after the emergence of whisker-related clusters of VPM thalamocortical axons. The mature pattern resolves earlier in rats than in mice. Taken together, these data reveal anatomical differences between mice and rats in the development and organization of POm inputs to barrel cortex, with implications for species differences in the nature and plasticity of lemniscal and paralemniscal information processing.