Natural History Study of Patients With Neurofibromatosis Type 2

Study Overview
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Brief Summary
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Objective With this prospective natural history study on neurofibromatosis type 2 (NF2) study, we hope to understand the factors leading to tumor progression and neurological disease burden in NF2. Study Population A total of 269 participants, ages 8-75, with a clinical or genetic diagnosis of NF2 will participate in this study. Design Study participants will be evaluated with a thorough physical and neurologic examination upon enrollment. This initial outpatient evaluation will include magnetic resonance imaging with contrast of brain and spine and blood collection for research use. Participants with measurable hearing will have audiology assessment performed during the initial visit. Participants with untreated vestibular schwannomas will have vestibular assessment performed during the initial visit. Genetic studies performed outside will be acceptable as confirmation of NF2 in enrolled patients. If needed to confirm NF2 with genetic studies, or for research purpose, whole genome/whole exome sequencing may be performed on blood obtained from subjects enrolled in this study. All participants will be evaluated by a speech language pathologist. Subjects will be followed as outpatients for up to ten years, during which clinical, and radiologic evaluation will be performed annually. Auditory testing will be performed annually for participants with measurable hearing. Participants with initially untreated vestibular schwannomas will be followed annually with vestibular testing. Speech and swallowing reassessments will be repeated if worsening of speech or swallowing is reported. Blood will be collected at each visit for blood biomarker testing Outcome measures We hope to understand the biologic basis for speech and swallowing dysfunction in patients with NF2. We will study and report the strength of association of MRI findings, clinical assessments cranial nerve deficits and speech/swallowing dysfunction. We hope to identify imaging biomarkers of hearing loss in NF2. We will attempt to discover the mode of peripheral neuropathy in patients with NF2. Lastly, we will attempt to discover previously unknown serum biomarkers associated with high tumor burden in NF2.

Detailed Description
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Objective With this prospective natural history study on neurofibromatosis type 2 (NF2) study, we hope to understand the factors leading to tumor progression and neurological disease burden in NF2. Study Population A total of 269 participants, ages 8-75, with a clinical or genetic diagnosis of NF2 will participate in this study. Design Study participants will be evaluated with a thorough physical and neurologic examination upon enrollment. This initial outpatient evaluation will include magnetic resonance imaging with contrast of brain and spine and blood collection for research use. Participants with measurable hearing will have audiology assessment performed during the initial visit. Participants with untreated vestibular schwannomas will have vestibular assessment performed during the initial visit. Genetic studies performed outside will be acceptable as confirmation of NF2 in enrolled patients. If needed to confirm NF2 with genetic studies, or for research purpose, whole genome/whole exome sequencing may be performed on blood obtained from subjects enrolled in this study. All participants will be evaluated by a speech language pathologist. Subjects will be followed as outpatients for up to ten years, during which clinical, and radiologic evaluation will be performed annually. Auditory testing will be performed annually for participants with measurable hearing. Participants with initially untreated vestibular schwannomas will be followed annually with vestibular testing. Speech and swallowing reassessments will be repeated if worsening of speech or swallowing is reported. Blood will be collected at each visit for blood biomarker testing Outcome measures We hope to understand the biologic basis for speech and swallowing dysfunction in patients with NF2. We will study and report the strength of association of MRI findings, clinical assessments cranial nerve deficits and speech/swallowing dysfunction. We hope to identify imaging biomarkers of hearing loss in NF2. We will attempt to discover the mode of peripheral neuropathy in patients with NF2. Lastly, we will attempt to discover previously unknown serum biomarkers associated with high tumor burden in NF2.

Official Title
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A Prospective Natural History Study of Patients With Neurofibromatosis Type 2 (NF2).

Conditions
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Neurofibromatosis

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: To be eligible for entry into the study, candidates must meet all the following criteria: Have the diagnosis of NF2 by established clinical criteria or genetic testing. Be between the age of 8 and 75. Have the capacity to undergo serial MRI scanning of the CNS without IV sedation. Able to give informed consent, or have a parent able to provide informed consent if a child. EXCLUSION CRITERIA: Candidates will be excluded if they: Have a clinically unstable condition that precludes serial clinical and imaging evaluation (i.e. Class 3 congestive heart failure, severe chronic renal insufficiency, severe chronic obstructive pulmonary disease). Cannot have an MRI scan due to an allergy or relative contraindication to MRI contrast agents. Have prior surgery or implant that involves metal clips or wires, which might be expected to cause tissue damage or produce image artifacts such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, and artificial heart valves. ABIs or cochlear implants are not approved by the NIH Radiology department for safe use on NIH scanners.. Have severe chronic renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73 m2), hepatorenal syndrome or post-liver transplantation. Are pregnant at time of intake visit (women of childbearing age will be tested with a urine pregnancy test).

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients must have the diagnosis of NF2 by established clinical criteria or genetic testing. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the natural history (clinical and radiographic) of nervous system tumors in NF2 | Clinical Variables (longitudinal: measured annually for each subject)a. Subjective speech and swallowing dysfunction (binary)b. Spinal cord function:Modified ASIA Motor Scalec. Ambulatory status:modified McCormick grading scaled. Overall function:Karnofsky Performance Statuse. NFTI-QOLf. Functional Independence Measure scale MRI Variables (longitudinal: measured annually for each subject):a. Tumor volume (continuous variable) for VS tumors, meningiomas, other schwannomas, ependymomas, and Total tumor burden (number and volume). Specific growth rates of tumors.b. FLAIR hyper-intensity MRI Variables (cross-sectional: measured at baseline and as needed for each subject):c. MRI of Right Upper and Lower Extremity Laboratory testing variables (longitudinal:measured annually for each subject):a. Audiometry Laboratory testing variables (cross-sectional:measured at baseline and as needed for each subject)b. EMG/NCV study valuesc. Vestibular testing Covariate variable:a. Ageb. Sex | annual for up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To identify the underlying causes, and patterns of progression of speech and swallowing problems in patients with NF2 | Self-reported swallowing deficits (binary, yes vs no) based on the last Visit (cross-sectional data) | Annual for up to 10 years | 
| To identify imaging biomarkers of hearing loss in patients with NF2 | MRI Variables (longitudinal: measured annually for each subject):a. Tumor volume (continuous variable) for VS tumors, meningiomas, other schwannomas, ependymomas, and Total tumor burden(number and volume). Specific growth rates of tumors.b. FLAIR hyper-intensity MRI Variables (crosssectional: measured at baseline and as needed for each subject | Annual for up to 10 years | 
| To identify the etiology of peripheral neuropathy in patients with NF2 | MRI images of the Right upper extremity will be evaluated for the presence of peripheral nerve lesions at baseline. These imaging findings will be evaluated with respect to EMG/NCV results. | Annual for up to 10 years | 
| To identify serum biomarkers of NF2 disease progression | determination of serum biomarker status and suspected biologic markers of disease progression using quantitative immunoassay or newer proteomic approaches | Annual for up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningioma, Ependymoma, Schwannoma, Spinal Cord Tumor, Vestibular Schwannoma, Natural History