Amy T Waldman

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (9)17.74 Total impact

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    ABSTRACT: The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
    09/2014; 13(9):936–948.
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    Amy M Lavery, Leonard H Verhey, Amy T Waldman
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials.
    Multiple sclerosis international. 01/2014; 2014:262350.
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    ABSTRACT: Abstract Objective: To assess the utility and safety of rituximab in paediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicentre retrospective study. Results: 144 children and adolescents (median age 8 years, range 0.7-17; 103 females) with NMDAR encephalitis (n=39), opsoclonus myoclonus ataxia syndrome (n=32), neuromyelitis optica spectrum disorders (n=20), neuropsychiatric systemic lupus erythematosus (n=18), and other neuro-inflammatory disorders (n=35) were studied at onset of neurological disease. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%) including Grade 4 (anaphylaxis) in three. 11 patients (7.6%) had an infectious adverse event (AE), including two with Grade 5 (death) and two with Grade 4 (disabling) infectious AE (median follow-up of 1.65 years (range 0.1-8.5). No patients developed progressive multifocal leukoencephalopathy. A definite, probable or possible benefit was reported in 125 of 144 (87%) patients. 17.4% of patients had a modified Rankin scale (mRS) of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data supports an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of Evidence: This study provides Class IV evidence that in paediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.
    Neurology 01/2014; · 8.30 Impact Factor
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    ABSTRACT: We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 12/2013; · 2.30 Impact Factor
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    ABSTRACT: Low-contrast letter acuity and optical coherence tomography (OCT) capture visual dysfunction and axonal loss in adult-onset multiple sclerosis (MS), and have been proposed as secondary outcome metrics for therapeutic trials. Clinical trials will soon be launched in pediatric MS, but such outcome metrics have not been well-validated in this population. To determine whether MS onset during childhood and adolescence is associated with measurable loss of visual acuity and thinning of the retinal nerve fiber layer (RNFL), whether such features are noted only in the context of clinical optic nerve inflammation (optic neuritis, ON) or are a feature of MS even in the absence of optic nerve relapses, and to define the optimal methods for such detection. Cross-sectional study. Monocular and binocular high- and low-contrast letter acuity and contrast sensitivity were assessed in a cross-sectional cohort of children (ages 5 to 17 years) with MS (N=22 patients, 44 eyes; 8 patients with a history of ON) and disease-free controls (N=29 patients; 58 eyes) from three academic centers. Binocular summation was determined by calculating the number of letters correctly identified using the binocular score minus the better eye score for each visual test. RNFL thickness was measured using OCT (Stratus OCT-3). Results were analyzed in terms of "eyes" as: MS ON+, MS ON-, and control eyes. Generalized estimating equation (GEE) regression models were used to compare patients to controls. Traditional high-contrast visual acuity scores did not differ between MS ON+, MS ON-, and controls eyes. MS ON+ eyes had decreased monocular (p<0.001) and decreased binocular (p=0.007) low-contrast letter acuity (Sloan 1.25% contrast charts) scores. Monocular visual acuity did not differ when comparing MS ON- and control eyes. The magnitude of binocular summation using low-contrast charts was similar for pediatric MS participants and controls and was not diminished in children with a history of ON. While the mean RNFL thickness for all MS eyes (103±17 μm) trended lower when compared to corresponding measures in control eyes (109±9 μm, p=0.085), we confirmed a highly significant reduction in mean RNFL thickness in MS eyes with a history of ON (86±22 μm, p<0.001). RNFL thickness of MS ON- eyes in pediatric MS patients (109±11 μm) did not differ from controls (p=0.994). Low-contrast letter acuity detects subtle visual loss in MS patients with prior ON, consistent with incomplete recovery, a finding further supported by RNFL loss in ON affected eyes. In MS patients with prior unilateral ON, binocular acuity is decreased; however, the magnitude of binocular summation is preserved, unlike adult-onset MS who exhibit a reduced capacity for visual compensation in the context of unilateral injury. Also unlike findings in adult-onset MS, we did not demonstrate RNFL thinning in ON- eyes of children and adolescents with MS. Further validation is required to confirm whether neurodegeneration of visual pathways occurs in the absence of relapse, and thus whether OCT will serve as a sensitive metric for such pathology in the pediatric and adolescent MS context.
    Multiple sclerosis and related disorders. 05/2013; 3(3):326-334.
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    ABSTRACT: New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool. Fifty-one IPMSSG members from 21 countries responded to the survey, and 50 approved the final statement. Consensus recommendations regarding use of existing first- and second-line therapies, as well as a proposed definition for inadequate treatment response, are presented. Recommendations for the use and evaluation of emerging therapies (currently in phase III clinical trials or recently approved for adult MS) are discussed. The IPMSSG endorses the inclusion of pediatric MS patients in trials evaluating appropriate new and emerging therapies. Mechanisms for conducting high-impact, multicenter studies, including long-term follow-up in pediatric MS, are required to ensure that all MS patients, irrespective of age, benefit from advances in MS therapeutics.
    Multiple Sclerosis 12/2011; 18(1):116-27. · 4.47 Impact Factor
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    ABSTRACT: To determine the relationships among age, unilateral versus bilateral simultaneous presentation, magnetic resonance imaging (MRI) lesions, and the risk of multiple sclerosis (MS) in children with optic neuritis. A systematic literature review and meta-analysis were performed by the use of a MEDLINE search to identify published studies containing individual patient data for children with optic neuritis. Age, laterality (unilateral vs bilateral simultaneous optic neuritis), presence of brain MRI abnormalities, and development of MS were recorded. Logistic regression was used to determine the relationships among these parameters. Fourteen studies met inclusion criteria. Data for 223 patients (age range 2-17.8 years) were analyzed. Unilateral optic neuritis occurred more frequently in older children but was not associated with an increased risk of MS, after adjusting for age (odds ratio [OR] = 1.9, P = 0.11; 95% confidence interval [CI], 0.9-4.3). For every 1-year increase in age, the odds of developing MS increased by 32% (OR = 1.3, P = 0.005; 95% CI, 1.1-1.6, adjusted for the presence of MRI lesions). The risk of MS was greater in children with abnormal brain MRI scans at presentation compared with normal MRIs (OR = 28.0, P < 0.001, 95% CI, 6.3-125.1, adjusted for age). The relationship between unilateral and bilateral optic neuritis and the development of MS is dependent on age. Older children and those with brain MRI abnormalities at presentation, are at greater risk for MS. Long-term follow-up of children with optic neuritis is needed to establish the true risk for the development of MS.
    Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 10/2011; 15(5):441-6. · 1.07 Impact Factor
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    ABSTRACT: Demyelinating diseases are a group of autoimmune inflammatory disorders affecting the central nervous system in adults and children; however, the diagnosis, evaluation, and treatment of these disorders are primarily based on adult data. The purpose of this study was to assess the practice patterns of US physicians who specialize in treating acquired central nervous system demyelinating diseases in children and adolescents. The Delphi technique was used to identify areas of consensus in management and treatment. Forty-two experts in the field participated in the process. Intravenous methylprednisolone was the first-line treatment of choice for acute episodes of all forms of demyelinating disease; however, consensus was lacking regarding specific dose, treatment duration, and use of an oral taper. First-line disease-modifying therapies for pediatric multiple sclerosis were interferons and glatiramer acetate, chosen based on perceived efficacy and tolerability, respectively. Areas lacking agreement among the expert panel and requiring further research are identified.
    Journal of child neurology 06/2011; 26(6):675-82. · 1.59 Impact Factor
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    ABSTRACT: The optic neuritis treatment trial (ONTT) and subsequent studies have had a tremendous impact on the treatment and prognosis of optic neuritis and multiple sclerosis in adults. The results of these studies have been extrapolated to children; however, pediatric data are sparse. Using the method of prospective preference assessment, the willingness of parents and medical professionals to enroll children in a hypothetical Pediatric ONTT was assessed using a mock consent form and questionnaire. A three-arm trial was proposed: (1) intravenous corticosteroids, (2) high-dose oral corticosteroids, and (3) an oral placebo. The forms were completed by 198 parents and 49 physicians. After reviewing the hypothetical scenario, trial design, risks and benefits, and alternatives to the study, 21% of parents would enroll their children in the trial whereas 98% of medical professionals would enroll their patients. With medical professional recommendation, 43% of parents would enroll their children. The manner in which this hypothetical trial was presented to parents, specifically with respect to the recommendation of their child's health care team, influenced a parent's willingness to participate.
    Frontiers in Neurology 01/2011; 2:75.