Characterizing Common Phenotypes Across the Childhood Dementia Disorders: A Cross-sectional Study From Two Australian Centers.

BACKGROUND: Childhood dementias are a group of rare pediatric conditions characterized by progressive neurocognitive decline. Quantifying and characterising phenotypes to identify similarities between specific conditions is critical to inform opportunities to optimize care and advance research. METHODS: This cross-sectional study recruited primary caregivers of children (<18 years) living with a dementia syndrome from neurology and metabolic clinics in Sydney and Adelaide, Australia. Sociodemographic and clinical data were collated. Behavior, eating, sleep, pain, and neurological disability were assessed using validated tools, including Strengths and Difficulties, Child Eating Behaviour, and Children's Sleep Habits questionnaires and visual analog of pain and modified Rankin scales. Data were analyzed with descriptive statistics. RESULTS: Among 45 children with 23 different dementia syndromes, the modified Rankin Scale demonstrated at least moderate neurological disability and functional dependence in 82% (37/45). Families reported delays in receiving an accurate diagnosis following initial symptoms (mean: 1.6 ± 1.4 years, range: 0-5 years). The most prevalent phenotypes included communication, comprehension, or recall difficulties (87%, 39/45); disturbances in sleep (80%, 36/45); appetite changes (74%, 29/39); mobility issues (53%, 24/45); and hyperactive behavior (53%, 21/40). Behavioral problems had a "high" or "very high" impact on everyday family life in 73% (24/33). CONCLUSIONS: Childhood dementia disorders share substantial behavioral, motor, sensory, and socioemotional symptoms, resulting in high care needs, despite their vast heterogeneity in age of onset and progression. Considering their unifying characteristics under one collective term is an opportunity to improve treatment, provide quality care, and accelerate research.

Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study.

BACKGROUND: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy. METHODS: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs. RESULTS: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects. CONCLUSIONS: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.

Sturge-Weber syndrome: from the past to the present.

Sturge-Weber syndrome is a rare sporadic neurocutaneous syndrome the hallmark of which is a facial port-wine stain involving the first division of the trigeminal nerve, ipsilateral leptomeningeal angiomata and angioma involving the ipsilateral eye. Our understanding of the disease process has vastly improved since it was first described in 1879, with recent identification of an activating somatic mutation in the GNAQ gene found in association with both Sturge-Weber syndrome and non-syndromic facial port-wine stain. Sturge-Weber syndrome is marked by a variable but usually progressive course in early childhood characterised by seizures, stroke-like episodes, headaches, neurological and cognitive deterioration, hemiparesis, glaucoma and visual field defects. More recently, the increased prevalance of otolaryngological, endocrine and emotional-behavioural issues have been established. Neurophysiology and neuroimaging studies provide information regarding the evolution of changes in Sturge-Weber syndrome over time. Early recognition and aggressive management of symptoms remains cornerstone in the management of this syndrome. An international collaborative effort is needed to maximise our understanding of the natural history and response to interventions in Sturge-Weber Syndrome.

Functional outcome measures for NF1-associated optic pathway glioma clinical trials.

OBJECTIVE: The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials. METHODS: The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials. RESULTS: Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed. CONCLUSIONS: The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.

Hearing and facial function outcomes for neurofibromatosis 2 clinical trials.

OBJECTIVES: Vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in >95% of patients. These tumors develop on the vestibulocochlear nerve and are associated with significant morbidity due to hearing loss, tinnitus, imbalance, facial weakness, and risk of early mortality from brainstem compression. Although hearing loss and facial weakness have been identified as important functional outcomes for patients with NF2, there is a lack of consensus regarding appropriate endpoints in clinical trials. METHODS: The functional outcomes group reviewed existing endpoints for hearing and facial function and developed consensus recommendations for response evaluation in NF2 clinical trials. RESULTS: For hearing endpoints, the functional group endorsed the use of maximum word recognition score as a primary endpoint, with the 95% critical difference as primary hearing outcomes. The group recommended use of the scaled measurement of improvement in lip excursion (SMILE) system for studies of facial function. CONCLUSIONS: These recommendations are intended to provide researchers with a common set of endpoints for use in clinical trials of patients with NF2. The use of common endpoints should improve the quality of clinical trials and foster comparison among studies for hearing loss and facial weakness.

Recommendations for imaging tumor response in neurofibromatosis clinical trials.

OBJECTIVE: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. METHODS: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. RESULTS: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. CONCLUSIONS: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.

Therapeutics for childhood neurofibromatosis type 1 and type 2.

OPINION STATEMENT: Neurofibromatosis type 1 (NF1) and type 2 (NF2) are genetically and medically distinct neurocutaneous disorders that are both associated with tumors affecting the central and peripheral nervous systems. NF1 has a frequency of 1 in 3,000, compared with 1 in 30,000 for NF2. Careful surveillance is important for both conditions, to allow early identification and treatment of complications. The most common and important problems in NF1 are cognitive impairment, optic pathway gliomas, plexiform neurofibromas, and orthopaedic issues. Early intervention and tailored educational programs are indicated for learning difficulties. Attention deficit hyperactivity disorder may be amenable to treatment with stimulant medication. A clinical trial is under way to evaluate lovastatin in the treatment of cognitive problems in children with NF1. Chemotherapy with vincristine and carboplatin is the current standard of care for symptomatic optic pathway gliomas, but new agents with improved efficacy are needed. Plexiform neurofibromas may be treated with surgery, but often recur. To date, no medical therapy has proven effective in limiting plexiform neurofibroma growth, but several candidate medications are under consideration in clinical trials. Malignant peripheral nerve sheath tumors may arise in preexisting plexiform neurofibromas, so changes in tumor growth or an increase in pain or focal neurologic deficit should prompt further investigation and early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy. Specialist surgical intervention may be needed for scoliosis and tibial pseudoarthrosis. In NF2, surgical treatment remains a cornerstone of management for symptomatic progressive vestibular schwannomas, meningiomas, and spinal tumors. Vascular endothelial growth factor inhibitors show promise for the treatment of vestibular schwannomas, with the aim of delaying surgery, and other targeted molecular therapies are becoming available as investigational options. Hearing aids and brainstem and cochlear implants have a role in optimizing functional hearing in some patients. Specialist ophthalmology input should be arranged to monitor for ophthalmologic complications. A coordinated effort is needed to enroll NF1 and NF2 patients in international multicenter clinical trials of promising new pharmacologic agents. Genetic testing is useful for prenatal diagnosis and may be important in understanding individual responses to novel medical therapies in the future. Effective transition to adult services is important, considering the likelihood of further complications in the adult years.