Multidisciplinary neurofibromatosis conference in the management of patients with neurofibromatosis type 1 and schwannomatosis in a single tertiary care institution.

OBJECTIVE: To evaluate the role of weekly neurofibromatosis (NF) multi-disciplinary conferences (MDC) on the diagnostic and therapeutic plan for patients with NF type 1 (NF1) and schwannomatosis (SWN). MATERIALS AND METHODS: This retrospective study reviewed patients with confirmed or suspected NF1 and SWN discussed in weekly MDC from March to July 2021. Demographic data collected included patient age, sex, pre-conference and post-conference diagnosis, radiological studies reviewed, and provider specialties in attendance. Outcomes reported included changes in imaging interpretation and treatment plans, changes in post-conference diagnosis relative to pre-conference diagnosis, and time to completion of the recommended change in treatment. RESULTS: Data from 17 MDC "pre-conference" lists included 75 patients (38 female, 37 males, mean age (years): 38 (range: 6-80)) with NF1 (52%, 39/75) and SWN (36%, 27/75) discussed over a total of 91 case reviews. 18.7% (14/75) of all patients had NF2-related SWN, and 17.3% (13/75) of all patients had non-NF2 SWN. The MDC led to changes in imaging interpretation in 18.7% and changes in patient management in 74.7% (diagnostic testing (n = 52), surgical plan (n = 24), medical treatment (n = 9), clinical trial status (n = 4), and radiation treatment (n = 1)) of cases. Among patients for whom a change in management was recorded, 91% (62/68) completed at least one recommendation (mean time to completion (days): 41.4 (range: 0-278)). CONCLUSION: Weekly MDC changes the diagnostic and therapeutic management of the majority of patients discussed (74.7%) and promotes a high adherence rate to recommendations (91%).

Understanding barriers to diagnosis in a rare, genetic disease: Delays and errors in diagnosing schwannomatosis.

Diagnosis of rare, genetic diseases is challenging, but conceptual frameworks of the diagnostic process can guide quality improvement initiatives. Using the National Academy of Medicine diagnostic framework, we assessed the extent of, and reasons for diagnostic delays and diagnostic errors in schwannomatosis, a neurogenetic syndrome characterized by nerve sheath tumors and chronic pain. We reviewed the medical records of 97 people with confirmed or probable schwannomatosis seen in two US tertiary care clinics. Time-to-event analysis revealed a median time from first symptom to diagnosis of 16.7 years (95% CI, 7.5-26.0 years) and median time from first medical consultation to diagnosis of 9.8 years (95% CI, 3.5-16.2 years). Factors associated with longer times to diagnosis included initial signs/symptoms that were intermittent, non-specific, or occurred at younger ages (p < 0.05). Thirty-six percent of patients were misdiagnosed; misdiagnoses were of underlying genetic condition (18.6%), pain etiology (16.5%), and nerve sheath tumor presence/pathology (11.3%) (non-mutually exclusive categories). One-fifth (19.6%) of patients had a clear missed opportunity for genetics workup that could have led to an earlier schwannomatosis diagnosis. These results suggest that interventions in clinician education, genetic testing availability, expert review of pathology findings, and automatic triggers for genetics referrals may improve diagnosis of schwannomatosis.

The development of the PlexiQoL: A patient-reported outcome measure for adults with neurofibromatosis type 1-associated plexiform neurofibromas.

BACKGROUND: To develop and validate a patient-reported outcome (PRO) measure of quality of life (QoL), specific to patients with Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibromas (pNFs), suitable for use in clinical efficacy trials. The study was conducted in parallel in the UK and US. METHODS: Qualitative interviews were conducted with patients to generate questionnaire content. Face and content validity of the draft scale was assessed by cognitive debriefing interviews (CDIs). A postal validation survey was conducted to identify the final version of the questionnaire (the PlexiQoL), establish its unidimensionality, and assess its psychometric properties. RESULTS: Thematic analysis was performed on 42 interview transcripts. Thirty-one CDIs revealed that patients found the draft scale to be comprehensible, relevant, and easy to complete. The postal validation survey was completed by 273 patients. Rasch analysis identified an 18-item unidimensional scale that showed excellent internal consistency, reproducibility, and sensitivity to differences in patient-perceived pNF severity, general health, and the use of pain medication. CONCLUSIONS: The PlexiQoL is the first disease-specific PRO assessing the ability of adults with NF-1 associated pNFs to meet their basic human needs. Clinical trials are planned to assess the sensitivity to change of the PlexiQoL in people undergoing treatment for pNFs.

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.

Current status and recommendations for imaging in neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are three clinically distinct tumor predisposition syndromes with a shared tendency to develop peripheral and central nervous system neoplasms. Disease expression and complications of NF1, NF2, and SWN are highly variable, necessitating a multidisciplinary approach to care in order to optimize outcomes. This review will discuss the imaging appearance of NF1, NF2, and SWN and highlight the important role that imaging plays in informing management decisions in people with tumors associated with these syndromes. Recent technological advances, including the role of both whole-body and localized imaging strategies, routine anatomic and advanced magnetic resonance (MR) imaging sequences such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping, and metabolic imaging techniques (MR spectroscopy and positron emission testing) are discussed in the context of the diagnosis and management of people with NF1, NF2, and SWN based on the most up-to-date clinical imaging studies.

Association between patient-reported outcomes and objective disease indices in people with NF2.

OBJECTIVE: The association between patient-reported outcomes and currently used clinical trial endpoints, including total vestibular schwannoma (VS) volume and word recognition score (WRS) in neurofibromatosis type 2 (NF2), is not known. METHODS: A prospective observational study enrolling adult patients with NF2 was conducted at a single specialty center. Measures included: NF2 impact on quality of life (NFTI-QOL), short form (SF)-36; total VS volume, WRS; provider- and patient-reported disease severity (ProvSev, PatSev) measured with an institutionally derived multi-item (e.g., symptom burden, age-of-onset, and fatality-risk) and single-item Likert (mild, moderate, severe) scale. RESULTS: Fifty-one patients were enrolled between June 2014 and August 2017. Mean age was 42.1 ± 18.2 years and 37.3% patients were male. Mean WRS was 74.4 ± 37.3%; mean total VS volume was 4.2 ± 5.2 cc. Additional lesions were common including meningioma (79.2%) and spinal ependymoma (39.6%). Mean NFTI-QOL score was 7.6 ± 4.9 and correlated with responses on the SF-36. NFTI-QOL also correlated well with PatSev (r = 0.63, p < 0.001) and both multi- and single-item ProvSev (r = 0.62, p < 0.001; r = 0.52, p < 0.001, respectively). A weak correlation was observed between NFTI-QOL and WRS (r = -0.34, p = 0.0156). There was no correlation with VS volume (r = 0.23, p = 0.15). CONCLUSIONS: The NFTI-QOL correlated well with multiple measures of disease severity but not commonly accepted endpoints for NF2 clinical trials including total VS volume in this US cohort of patients with NF2. This suggests that the NFTI-QOL captures components of the patient experience not sufficiently represented by objective measures of disease and underscores the important and complementary role of patient-focused measures in therapeutic outcome assessment in people with NF2.

A qualitative study of the impact of plexiform neurofibromas on need fulfilment in adults with neurofibromatosis type 1.

OBJECTIVE: To explore the impact of plexiform neurofibromas on the lives of adults with neurofibromatosis type 1. BACKGROUND: Neurofibromatosis type 1 is a complex neurogenetic syndrome that affects many aspects of health and functioning. A common manifestation of neurofibromatosis type 1 is plexiform neurofibromas, non-cancerous tumours that can cause disfigurement, pain and neurologic disability. Patient-reported outcome measures used in this condition have addressed symptoms and functional ability but not how the condition affects patients' lives, particularly, their ability to meet their human needs. METHODS: Unstructured qualitative interviews were conducted with adults with neurofibromatosis type 1-associated plexiform neurofibromas in the United Kingdom and United States. Interviewees were encouraged to describe how plexiform neurofibromas affected their ability to meet their needs. Interviews were audio-recorded and transcribed verbatim. The UK and US transcripts were combined and theoretical thematic analysis was conducted. RESULTS: In all, 42 interviews (United Kingdom = 20, United States = 22) were conducted. Transcripts revealed 696 statements on the impact of plexiform neurofibromas on need fulfilment. Five major themes emerged: appearance, relationships, independence, role fulfilment and pleasure. CONCLUSION: Neurofibromatosis type 1-associated plexiform neurofibromas have a major effect on individuals' ability to meet their needs. An understanding of need fulfilment will complement information generated from traditional patient-reported outcome measures, particularly in a multi-faceted syndrome such as neurofibromatosis type 1.

Voice and Swallowing Dysfunction in Neurofibromatosis 2.

Objective Neurofibromatosis 2 (NF2) is a neuro-oncologic condition that presents with bilateral vestibular schwannomas of the cerebellopontine angle (CPA). Voice and swallowing impairment can occur from direct involvement or compression of the vagus nerve or as the result of surgical excision of CPA tumors. The objectives in this study are to (1) assess the prevalence of voice and swallowing impairments and (2) analyze the effects of vagal dysfunction in patients with NF2. Study Design Cross-sectional. Setting Academic tertiary care center. Subjects and Methods Patients at a neurofibromatosis center were mailed Voice Handicap Index and Sydney Swallow Questionnaire surveys. Stroboscopic, voice, and swallowing evaluations were performed for patients who elected to participate in screening exams. Results There were high rates of self-assessed and objective voice and swallowing handicaps in this population. Fourteen of 40 (35%) patients had a self-assessed voice handicap, and 20 of 40 (50%) patients had a self-assessed swallow handicap. Vocal fold motion impairment (VFMI) was observed in 22 of 31 (71%) patients examined, with 27 of 62 (44%) possible vocal cords affected. Velopharyngeal insufficiency (45%) and piriform sinus pooling or residue (39%) were seen in a significant percentage of patients. There was a significant relationship between vocal cord motion impairment and CPA surgical intervention ipsilateral to the impairment ( P = .002). The presence of VFMI was strongly associated with voice ( P = .002) and swallowing ( P = .01) impact on quality of life. Conclusion Speech and swallowing impairments are highly prevalent in patients with NF2, cause significant impact on quality of life, and are most commonly related to surgical interventions in the CPA region.

Low-grade Schwann cell neoplasms with leptomeningeal dissemination: clinicopathologic and autopsy findings.

Leptomeningeal dissemination of low-grade Schwann cell neoplasms is an exceptionally rare occurrence and has not been well documented in the literature. We encountered 2 cases of leptomeningeal dissemination of low-grade Schwann cell neoplasms. Patient 1 was a 63-year-old woman with neurofibromatosis type 1 and a progressive low-grade malignant peripheral nerve sheath tumor developing from a diffuse/plexiform orbital neurofibroma that arose in childhood. The neoplasm demonstrated local and leptomeningeal dissemination intracranially leading to the patient's death. There was partial loss of H3K27 tri-methylation, p16 and collagen IV. Patient 2 was a 60-year-old man without neurofibromatosis type 1 who presented with cranial nerve symptoms and a disseminated neoplasm with a Schwann cell phenotype. The neoplasm stabilized after irradiation and chemotherapy, but the patient died of medical complications. Autopsy findings documented disseminated leptomeningeal disease in the intracranial and spinal compartment. H3K27M tri-methylation was preserved. The clinicopathologic and autopsy findings are studied and presented, and the literature is reviewed.