Diagnostic Algorithm for Pediatric Headaches: A Clinical Improvement Initiative.

BACKGROUND: The widespread variation in diagnosing primary headache disorders in children and adolescents results in reduced quality and high costs. Defining an algorithm for primary headache diagnoses in children and adolescents is part of a larger initiative to standardize and improve care. The aim of this algorithm was to increase the accuracy of headache diagnosis by formal criteria to more than 80% of patient encounters. METHODS: A team of headache specialists, nurse practitioners, nurses, data analysts, and business specialists developed an algorithm based on available scientific evidence. This algorithm was vetted and adapted by the neurology faculty and headache specialists until final consensus was reached. Following three months of testing and validation, the algorithm was disseminated to general pediatric neurology clinics. The following information was gathered: percent of encounters utilizing the algorithm, percentage of encounters with appropriate diagnosis by formal criteria, percentage of encounters with appropriate testing ordered, and average cost per headache visit. RESULTS: Correct diagnosis of primary headache by International Classification of Headache Disorders-3 criteria improved from 72% to 90% and appropriate testing improved from 80% to 94%. By the end of analysis, 94% of encounters were correctly implementing the algorithm. A year-long tracking revealed decreased cost of headache evaluation by 6% compared with the year prior. CONCLUSIONS: A standardized algorithm improved the diagnostic accuracy in general child neurology clinics. Expanding the algorithm to primary care and pediatric emergency rooms could have a greater impact on headache evaluation and diagnosis; this should result in improved care and outcomes with reduced cost.

Pediatric brain aneurysms: a review of 1458 brain MR angiograms.

PURPOSE: To evaluate clinical and imaging characteristics of pediatric brain aneurysms. MATERIALS AND METHODS: A retrospective review of 1458 MR angiograms of pediatric patients (≤18 years old) obtained between 2006 and 2021 was performed. A non-infundibular arterial luminal outpouching larger than 1mm in size was identified as an "Intracranial aneurysm." Patient demographics, clinical presentations, and predisposing risk factors, including family history and underlying medical conditions, were reviewed. MRA images were analyzed for aneurysm location, number, maximum diameter, and interval changes on follow-up. RESULTS: Forty-nine (3.3%) patients (30 females, 19 males) with 64 intracranial aneurysms were identified with an average age of 13.71 ± 3.67 years. Eleven (22.4%) patients had multiple aneurysms. An underlying systemic illness was observed in 81.6% (40/49) cases, with sickle cell disease as the most frequent (25/49, 51%) diagnosis. A first-degree family history of intracranial aneurysms was recognized in 36/1458 (2.5%) patients. However, no intracranial aneurysm was found in this group. While 02/49 (4%) patients presented with acute SAH, headache was the most common (16/49, 32.7%) symptom at presentation in unruptured cases. The majority (47/64, 73.4%) of the aneurysms were located in the anterior circulation, with the ICA ophthalmic segment being most frequently (24/47, 51%) involved. Most (54/64, 84.4%) aneurysms were smaller than 4mm in size at the time of diagnosis. At least one follow-up MRA was obtained in 72.3% (34/47) of the unruptured aneurysms cohort. There was no change in the aneurysm size and morphology in 31/34 (91.2 %) patients over an average imaging follow-up of 39.6 months. Three (6%) patients demonstrated an interval increase in the aneurysm size. SAH patients (n=2) and two unruptured aneurysm patients with an interval increase in size were successfully treated with endovascular techniques. CONCLUSION: Female predominance with a higher frequency of small and unruptured intracranial aneurysms was recognized in our cohort. A higher incidence of an underlying systemic illness, especially sickle cell disease, was also noted. Most intracranial aneurysms in children appear to remain stable. However, there seems to be the risk of an aneurysm size increase which warrants regular clinical and imaging follow-up.

Impact of magnetic resonance angiography parameters on stroke prevention therapy in pediatric patients with sickle cell anemia.

BACKGROUND: Degree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which has significant risks. Flow artifact, intrinsic to magnetic resonance angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol for patients with SCA. METHODS: A standardized MRA scanning protocol with an echo time of less than 5 ms was implemented at Montefiore Medical Center (MMC), NY in May 2016. Retrospective chart review identified 21 pediatric patients with SCA, with an MRA head both pre- and post-May 2016. Arterial stenosis on MRA, machine parameters, and treatment plans were compared pre- and post-implementation. RESULTS: Ten of the 21 patients met inclusion criteria. Previously seen stenosis was re-classified to a lower degree in six of the 10 patients, leading to discontinuation of transfusions in five patients. No patients required escalation of therapy to chronic transfusions. CONCLUSION: Optimizing flow artifact by decreasing echo time to less than 5 ms can improve accurate interpretation of cerebrovascular disease, and ensure appropriate treatment plans are in place for stroke prevention. This is especially important for implementing "TCD With Transfusions Changing to Hydroxyurea (TWiTCH)" clinical trial results in the real-world setting.

Clinical Reasoning: A Teenager With Right-Sided Headache and Periorbital Changes.

While migraine is the most common headache disorder in children and adolescents presenting to a neurologist, other primary headache disorders are important to recognize. Trigeminal autonomic cephalalgias represent a rare group of primary headache disorders with different characteristics, workup, and management. In this study, we present an adolescent with 1 common and 1 unique headache phenotype, followed by a guided discussion of the differential diagnoses, workup, treatments, and a brief summary of further management considerations.

Management of Chronic Migraine in Children and Adolescents: Where are We in 2022?

Migraine is a neurological disorder that affects millions of children and adolescents worldwide. Chronic migraine is a subtype of migraine in which patients experience headaches for more days than not each month, with accompanying symptoms of phonophobia, photophobia, nausea or vomiting for most of these headaches. The burden and impact of chronic migraine in the daily lives of children and adolescents is substantial, requiring a holistic, multidisciplinary, and biopsychosocial approach to conceptualization and treatment. The purpose of this review is to provide a comprehensive "2022" overview of acute and preventive treatments for the management of chronic migraine in youth. We first describe diagnostic criteria for chronic migraine and highlight the state of evidence for acute and preventive treatment in children and adolescents. We then discuss emerging treatments currently receiving rigorous clinical research effort, special considerations for the treatment of chronic migraine in children and adolescents, and avenues for improving existing treatments and expanding access to evidence-based care.

The diagnostic spectrum of ATP1A3-related disorders: 3 new patients.

BACKGROUND: ATP1A3-related disorders are rare but increasingly recognized syndromes with overlapping phenotypes. CLINICAL OBSERVATIONS: A male child and his mother with c.2452G>A (p.Glu818Lys) mutation and an unrelated child with c.2428A>T (p.Ile810Phe) mutation in the ATP1A3 gene are reported. RESULTS: The first child presented with fever-induced flaccid unresponsiveness and the diagnosis was made after extensive negative workup except for abnormal EMG showing low amplitude motor responses with acute denervation; his symptomatic mother went undiagnosed for thirty years until his diagnosis. An unrelated male child presented with symptoms most consistent with the rapid-onset dystonia-Parkinsonism (RDP) phenotype but with intermediate features of alternating dystonia with choreoathetoid movements two years after a c.2428A>T (p.Ile810Phe) mutation was found. CONCLUSION: ATP1A3-related disorders have variable manifestations and can remain undiagnosed for decades. Treatment remains mostly supportive. With the increasing use of genetic testing for broad indications, further research into effective therapies is necessary.

Risk factors for subsequent febrile seizures in the FEBSTAT study.

OBJECTIVES: To identify risk and risk factors for developing a subsequent febrile seizure (FS) in children with a first febrile status epilepticus (FSE) compared to a first simple febrile seizure (SFS). To identify home use of rescue medications for subsequent FS. METHODS: Cases included a first FS that was FSE drawn from FEBSTAT and Columbia cohorts. Controls were a first SFS. Cases and controls were classified according to established FEBSTAT protocols. Cumulative risk for subsequent FS over a 5-year period was compared in FSE versus SFS, and Cox proportional hazards regression was conducted. Separate analysis examined subsequent FS within FSE. The use of rescue medications at home was assessed for subsequent FS. RESULTS: Risk for a subsequent FSE was significantly increased in FSE versus SFS. Any magnetic resonance imaging (MRI) abnormality increased the risk 3.4-fold (p < 0.05), adjusting for age at first FS and FSE and in analyses restricted to children whose first FS was FSE (any MRI abnormality hazard ratio [HR] 2.9, p < 0.05). The risk for a second FS of any type or of subsequent FS lasting >10 min over the 5-year follow-up did not differ in FSE versus SFS. Rectal diazepam was administered at home to 5 (23.8%) of 21 children with subsequent FS lasting ≥10 min. SIGNIFICANCE: Compared to controls, FSE was associated with an increased risk for subsequent FSE, suggesting the propensity of children with an initial prolonged seizure to experience a prolonged recurrence. Any baseline MRI abnormality increased the recurrence risk when FSE was compared to SFS and when FSE was studied alone. A minority of children with a subsequent FS lasting 10 min or longer were treated with rectal diazepam at home, despite receiving prescriptions after the first FSE. This indicates the need to further improve the education of clinicians and parents in order to prevent subsequent FSE.

Comparison of perioperative outcomes and complication rates between conventional versus robotic-assisted laparoscopy in the evaluation and management of early, advanced, and recurrent stage ovarian, fallopian tube, and primary peritoneal cancer.

OBJECTIVE: The objective of this study was to examine perioperative outcomes, including complication rates, of conventional laparoscopy (CL) versus robotic-assisted laparoscopy (RALS) in the evaluation and management of early, advanced, and recurrent ovarian, fallopian tube, and peritoneal cancer. METHODS: This is a retrospective analysis of a prospectively maintained database of surgery performed from July 2008 to December 2012. Sixty-three women had 83 surgeries performed; 22 surgeries for early-stage disease (International Federation of Gynecology and Obstetrics stage I) and 61 for advanced and/or recurrent disease. RESULTS: Of the 22 for early stage, 10 were CL, 9 were RALS, and 3 were laparoscopy converted to laparotomy (LP). There was no significant difference between CL and RALS in estimated blood loss (EBL, P = 0.27) or length of stay (LOS, P = 0.43); however, both had significantly less EBL (P = 0.03 and 0.03, respectively) and LOS (P = 0.03 and 0.03) than LP. There was no difference in OR time among the groups (P = 0.79). One patient (33%) had an intraoperative complication in LP. One patient (10%) had a postoperative complication in CL, 2 (22%) in RALS, and 1 (33%) in LP, with no significant difference (P = 0.61).Among the 42 patients with advanced/recurrent disease, 61 surgeries were performed: 14 diagnostic procedures and 47 cytoreductive surgeries. Of the 47, there was no difference in operating room time (P = 0.10). There was no difference in EBL or LOS between CL and RALS (P = 0.82, P = 0.87); however, both were less in CL (P < 0.001 and P = 0.02) and RALS (P = 0.01 and P = 0.02) compared with LP. There were 5 (63%) intraoperative transfusions in LP and none in CL or RALS. When including all surgeries for advanced/recurrent disease, there was 1 intraoperative complication (12%) in LP. There was no difference in postoperative complications between groups (P = 0.89); 8 patients (19%) had postoperative complications in CL, 2 (18%) in RALS, and 2 (25%) in LP. Overall, there were no grade 4 or 5 complications and no perioperative or intraoperative deaths. CONCLUSIONS: In our experience, perioperative outcomes are comparable between CL and RALS in both early and advanced/recurrent disease and not inferior to laparotomy, making CL and RALS an acceptable approach in selected patients.

Long-term post-stroke changes include myelin loss, specific deficits in sensory and motor behaviors and complex cognitive impairment detected using active place avoidance.

Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be important for cognitive behavioral control necessary for complex APA learning.

Fibronectin matrix assembly suppresses dispersal of glioblastoma cells.

Glioblastoma (GBM), the most aggressive and most common form of primary brain tumor, has a median survival of 12-15 months. Surgical excision, radiation and chemotherapy are rarely curative since tumor cells broadly disperse within the brain. Preventing dispersal could be of therapeutic benefit. Previous studies have reported that increased cell-cell cohesion can markedly reduce invasion by discouraging cell detachment from the tumor mass. We have previously reported that α5ß1 integrin-fibronectin interaction is a powerful mediator of indirect cell-cell cohesion and that the process of fibronectin matrix assembly (FNMA) is crucial to establishing strong bonds between cells in 3D tumor-like spheroids. Here, we explore a potential role for FNMA in preventing dispersal of GBM cells from a tumor-like mass. Using a series of GBM-derived cell lines we developed an in vitro assay to measure the dispersal velocity of aggregates on a solid substrate. Despite their similar pathologic grade, aggregates from these lines spread at markedly different rates. Spreading velocity is inversely proportional to capacity for FNMA and restoring FNMA in GBM cells markedly reduces spreading velocity by keeping cells more connected. Blocking FNMA using the 70 KDa fibronectin fragment in FNMA-restored cells rescues spreading velocity, establishing a functional role for FNMA in mediating dispersal. Collectively, the data support a functional causation between restoration of FNMA and decreased dispersal velocity. This is a first demonstration that FNMA can play a suppressive role in GBM dispersal.