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Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis… Sellmer, Laura; Farschtschi, Said; Marangoni, Marco; Heran, Manraj K S; Birch, Patricia; Wenzel, Ralph; Mautner, Victor-Felix; Friedman, Jan M Apr 23, 2018

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RESEARCH Open AccessSerial MRIs provide novel insight intonatural history of optic pathway gliomasin patients with neurofibromatosis 1Laura Sellmer1* , Said Farschtschi2, Marco Marangoni3, Manraj K. S. Heran3, Patricia Birch1, Ralph Wenzel4,Victor-Felix Mautner2† and Jan M. Friedman1†AbstractBackground: Optic pathway gliomas (OPGs) are present in 20% of children with neurofibromatosis 1 (NF1) but are lessfrequently observed in adults. Our goal was to determine the natural history of OPGs in children and adults with NF1.Results: We analyzed the features of OPGs and other intracranial lesions on 1775 head MRI scans of 562 unselectedadults and children with NF1 collected between 2003 and 2015. 52 (9.3%) of 562 patients in this study had an OPGdiagnosed on their MRI. The median age at first scan with an OPG present was 12.7 years. Of the 52 OPG patients, theintraorbital optic nerves were affected in 29 patients (56%), the prechiasmatic optic nerves were affected in 32 patients(62%), the optic chiasm was affected in 17 patients (33%) and the optic radiations were affected in 19 patients (37%). 29patients had two or more areas affected. One patient had a newly-appearing OPG, and 1 patient showed progression.The rate of progression over 5 years was 2.4% (95% CI: 0.4% to 16%). Four patients showed partial regression of theirOPGs, but we observed no case of complete regression during this study. The rate of regression over 5 years was 8.9%(95% confidence intervals: 2.8% to 26%). We found the presence of UBOs and the presence of OPGs in individual patientsto be highly associated (p = 0.0061).Conclusion: OPGs are more common in older adults with NF1 than previously thought. The occurrences of unidentifiedbright objects (UBOs) and asymptomatic OPGs are associated with each other. This suggests the possibility that OPGs thatremain asymptomatic may differ pathogenically from those that become symptomatic.Keywords: Optic pathway glioma, Neurofibromatosis 1, Cohort study, Glioma, Adults, ChildrenBackgroundNF1 is a dominantly inherited multisystem disorderaffecting 1 in 3500 individuals [1]. It is caused by muta-tions in NF1, a large gene located on the long arm ofchromosome 17 [2–4]. NF1 is a neurocutaneous dis-order characterized by the development of dermal andplexiform neurofibromas and café-au-lait spots [5]. Oneof the most serious manifestations of NF1 in children isthe development of optic pathway gliomas (OPGs).These tumours affect approximately 20% of all childrenwith NF1 [6] and can lead to a loss of vision, proptosis,or precocious puberty. Fortunately, however, thesetumours remain asymptomatic in the majority of affectedchildren. It is currently not recommended to screen chil-dren with NF1 routinely by MRI for optic pathwaygliomas, as the vast majority of tumours are indolent, andearly detection does not improve visual outcomes [7].Factors such as tumour location [8] and changes in tis-sue microstructure [9] have been proposed to predictwhich OPGs will become symptomatic; however, thesefindings remain controversial. This is largely because thenatural history of OPGs in people with NF1 has not beenthoroughly characterized: There are no large studies ofadult NF1 patients with OPGs, and we do not even knowthe prevalence of this tumour in adults with NF1.In this study, we used routine MRIs to investigate theprevalence and natural history of optic pathway gliomasin children and adults with NF1.* Correspondence: lsellmer@cfri.ca†Equal contributors1Department of Medical Genetics, BC Children’s Hospital, University of BritishColumbia, 4480 Oak Street, Vancouver, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Sellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 https://doi.org/10.1186/s13023-018-0811-9MethodsPatientsAll NF1 patients seen in the NF outpatient departmentof the University Hospital Hamburg-Eppendorf between2003 and 2015 were offered whole-body and head MRIsas part of a routine tumour monitoring protocol [10].Since MRIs were offered to all patients independent oftheir clinical symptoms, the images are representative ofthe patient population seen in the clinic. Informed con-sent was obtained from all subjects, and the ethical com-mittees of the Medical Chamber of Hamburg and theUniversity of British Columbia approved the study.Magnetic resonance imaging (MRI)To evaluate the extent of optic gliomas, we defined fourlocations: intraorbital optic nerves, prechiasmatic opticnerves, chiasm, and optic tracts/optic radiations. A gli-oma of the optic pathway was diagnosed if there washyperintensity on T2-weighted images or if theyenhanced after contrast injection. A tumour was definedas being multifocal of it was present in two or more un-connected sections of the optic pathway.Based on the 1775 clinical MRI reports, a list of pa-tients was generated who had been clinically diagnosedwith OPG. All head MRIs from these patients were re-evaluated by two neuroradiologists in Canada (M.M. andM.K.S.H.), and the presence of OPGs in each individualMRI study was established by consensus using the cri-teria described above.Features extracted from MRIs and clinical recordsClinical features extracted from the MRI reports of all 562patients included: Presence of OPG, presence of non-opticgliomas, presence of unidentified bright objects (UBOs)and presence of plexiform neurofibromas (PNs) on the cor-responding whole-body MRI examination. The presence ofsubcutaneous neurofibromas in patients with OPG was de-termined from the corresponding whole-body MRI.The last visual acuity measurements during the studyperiod were used to determine the presence or absenceof loss of vision and visual field defects.Descriptive statistical analysisPatients were divided into 10-year age groups andcounted only once per age group. 95% confidence inter-vals of OPG prevalence were calculated as ±1.96 stand-ard deviations of a binomial distribution.Multiple logistic or linear regression was performed toidentify factors associated with OPG presence or vol-ume. Natural log transformation was applied to thetumour volumes to achieve normal distribution for lin-ear regression. Predictor variables for logistic regressionwith presence of OPG as the outcome variable were ageat first scan with OPG present and the presence of non-optic gliomas, UBOs, or plexiform neurofibromas. Pre-dictor variables for analysis of OPG volume were age atfirst scan with OPG present, and the presence of non-optic gliomas, UBOs, plexiform neurofibromas or sub-cutaneous neurofibromas.We used the Kaplan-Meier method to calculate thecumulative rates and 95% confidence intervals of OPGprogression or regression within 5 years of first MRIdiagnosis. The log-rank test was used to assess differ-ences between the rates of progression or regression inpatients under 20 years of age and those over 20 years ofage. These analyses were performed with IBM SPSS Sta-tistics version 24.UBO prevalence in patients with or without OPGs wascompared using the Mantel-Haenszel test. Each patientwas counted once after stratification into a single agegroup for this analysis: 0–9.99, 10.0–19.99, 20.0–29.99,30.0–39.99 or ≥ 40 years old at the time of first MRI orfirst MRI on which an OPG was seen in the study. Thecalculation was performed using IBM SPSS Statisticsversion 24.Results with p ≤ 0.05 were considered to be statisticallysignificant.ResultsDemographics562 NF1 patients (264 males and 298 females) were in-cluded in this study. A total of 1775 whole-body andhead MRI examinations were performed on these pa-tients between 2003 and 2015, with a median follow-uptime of 3.7 years (range 0 to 13.0 years) and a mediannumber of 3 scans per person (range 1 to 13 scans). Atthe time of the MRI scan, patient ages ranged from 0.4to 72.8 years. During the study, 75 patients were lost tofollow-up or died of a reason unrelated to OPG, equal-ing a dropout rate of 13.3%.Prevalence of optic pathway glioma per age group56 patients received a clinical diagnosis of OPG based ontheir brain MRIs. In 52 patients, two independent neuro-radiologists confirmed the diagnosis of OPG using thestudy criteria (see Table 1 and Additional file 1: Table S1).The overall prevalence of OPG among NF1 patients inthis study was 9.3%. The prevalence was highest amongchildren aged 10 or younger and declined with advancingage (Fig. 1a). The median follow-up of all NF1 patientswho had OPGs was 5.2 years (range: 0–13.0 years), with atotal of 283.2 patient years of follow-up.Description of OPGsAn overview of the clinical features of all OPGs is pre-sented in Table 1 (symptomatic patients) and Additionalfile 1: Table S1 (asymptomatic patients). Of the 48 gli-omas that affected the optic nerves, 29 were unilateralSellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 2 of 9Table 1 Features of symptomatic optic pathway gliomas in 17 of 52 OPG patients. OPG location indicates extent after shrinkage inpatients with regression or extent after growth in patients with progression of the tumour. Details on asymptomatic OPG patientscan be found in Additional file 1: Table S1PatientnumberSex Age atfirstscan(years)OPG location Enhancement Changesduringfollow-upSymptoms Age atsymptomonset (Inyears)Treatment Changes aftertreatment4 F 19.7 Left intraorbital ON No Stable Reduced vision in left eye 3 – –5 F 10.8 Chiasm Avid Stable Reduced vision and visualfield defects in both eyes11 Vincristin,carboplatineTumourshrinkage andimprovementof vision13 M 6.2 Right prechiasmatic ON,chiasm, right radiationsAvid Stable Reduced vision in botheyes, visual field defect inright eye, prematurepuberty6 Vincristin,carboplatine,leuprorelinImprovedvision14 M 25 Right and left intraorbitalONNo Stable Reduced vision in left eye,visual field defect in lefteye, hydrocephalus4 – –17 F 8.7 Right and left intraorbitalONNo Stable Reduced vision in botheyes5 Vincristin,carboplatineImprovedvision18 M 30.3 Right and left prechiasmaticON, chiasm, right and leftradiationsDiffuse Stable Reduced vision in rightand left eye, visual fielddefects in both eyes6 – –29 M 18.1 Left prechiasmatic ON,chiasm, right and leftradiationsMild Stable Blind in left eye, reducedvision and visuals fielddefect in right eye6 – –30 F 15.3 Right and left intraorbitalON, right and, leftprechiasmatic ON, chiasm,right and left radiationsDiffuse Stable Reduced vision in botheyes, visual field defect inleft eyeUnknown Vincristin,carboplatineDecreasedvision31 M 48.9 Right and left intraorbitalON, right and leftprechiasmatic ONNo contrastusedStable Blind in both eyes 1.5 – –33 F 34.6 Right prechiasmatic ON,chiasmNo Stable Reduced vision in righteye3 – –35 F 25.4 Right intraorbital ON, rightprechiasmatic ON, chiasm,right radiationsMild Stable Blind in right eye, reducedvision and visual fielddefect in left eye4 – –39 F 15.1 Left prechiasmatic ON,chiasm, left radiationsNo contrastusedStable Blind in left eye, reducedvision and visual fielddefect in right eye11 Radiationand surgeryDecreasedvision41 F 34.5 Left prechiasmatic ON No Stable Reduced vision in botheyes, visual field defects inboth eyes, diffusehydrocephalus5 – –43 M 12.3 Right and left intraorbitalON, right and leftprechiasmatic ON, chiasm,right radiationsNo Stable Reduced vision in rightand left eye, visual fielddefect in right eye, diffusehydrocephalus6 Vincristin,carboplatineStable vision45 M 46.1 Right intraorbital ON, rightprechiasmatic ON, chiasmNo Stable Reduced vision in botheyes, visual field defects inboth eyes4 – –49 M 44.6 Left intraorbital ON Avid Stable Blind in left eye 34 Surgery Decreasedvision50 F 25.3 Right prechiasmatic ON No Stable Reduced vision in righteyeUnknown – –Abbreviations: ON Optic nerveSellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 3 of 9and 19 were bilateral. 12 of 52 OPGs were multifocal,equaling a total number of 64 tumours. Tumour volumesper patient ranged from 95.4 mm3 to 9255 mm3, with amedian tumour volume of 879 mm3. 45 of the 52 OPGpatients had their MRI scans performed with contrastenhancement: 34 of these patients showed noenhancement, 2 patients showed diffuse enhancement, 3patients showed mild enhancement and 6 patients showedavid enhancement of their tumours. The clinical head andwhole-body MRI reports included in this study noted thepresence of UBOs in 246 (43.8%) and plexiform neurofibro-mas in 321 (57.1%) patients. Subcutaneous neurofibromaswere seen in 22 (42%) of the 52 NF1 patients with OPG(these tumours were only evaluated in patients with OPG).17 of the 52 patients with OPGs were symptomatic.All experienced vision decline, while 13 also had visualfield defects. Patients with symptomatic OPGs receivedone MRI per year, with ophthalmologic assessments in be-tween. During those assessments visual acuity testing, vis-ual field testing and occasionally OPG was performed. Ofthese 17 patients with symptomatic OPG, 7 were treated:Five received chemotherapy with vincristine and carbopla-tin, one underwent surgery, and one underwent surgeryand radiation. Surgery was reserved for cases with pro-nounced visual decline and rapidly growing tumours. Theradiation treatment performed on one patient took placein 1996 before the high risk of secondary malignancy inpeople with NF1 who are treated with radiotherapy wasappreciated. One patient (Patient 13) experienced prema-ture puberty and was treated with leuprorelin.We investigated the prevalence of symptomatic andasymptomatic OPGs per 10-year age group (Fig. 1b).Fig. 1 Prevalence of optic glioma per age group. a Total prevalence of OPG per age group. Error bars are 95% confidence intervals of a binomialdistribution. b Prevalence of asymptomatic and symptomatic OPGs per age group. Error bars are 95% confidence intervals of abinomial distributionSellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 4 of 9Asymptomatic OPGs are very prevalent in young chil-dren, and their frequency decreases with increasing ageuntil adulthood. In contrast, the prevalence of symptom-atic tumours remains stable throughout all age groups.Non-optic gliomas were seen in 34 of the 562 NF1 pa-tients included in this study: nine (17%) of the 52 pa-tients with OPG but only 25 (5.15%) of 485 withoutOPG (p = 0.001).Newly-appearing OPGsThere was only one patient (Patient 8) with an optic gli-oma that appeared during the course of this study (Fig. 2).After its first appearance at 2.0 years of age, the gliomawas avidly enhancing. 3.5 years later the enhancement de-creased from avid to diffuse. The patient remained asymp-tomatic throughout follow-up.OPG progressionOnly one of the 52 NF1 patients with OPG (Patient 37)had a tumour that increased in volume during the studyperiod (Fig. 3). The rate of progression was estimated as2.4% over 5 years (95% confidence intervals: 0.4% to16%). There was no significant difference in the cumula-tive rates of progression between children (< 20 years ofage) and adults (≥20 years of age) (p = 0.42).OPG regressionFour patients (Patients 3, 24 and 27) with OPG showedspontaneous shrinkage of their tumours during theperiod of observation (for Patient 3 see Fig. 4). The rateof regression was estimated as 8.9% over 5 years (95%confidence intervals: 2.8% to 26%). As with progression,there was no significant difference in the cumulativerates of regression between children and adults (p = 0.17). All instances of OPG regression occurred in patientsunder the age of 20 years, although only 54% of thepatient-years of observation took place in this age group(p = 0.002). In at least three of these four patients (Pa-tients 24, 27 and 48), the OPG showed enhancementprior to its shrinkage (no contrast enhanced studies wereperformed in Patient 3 after his first scan).Association of OPG presence and volume with otherfeatures observed on MRI examinationWe performed multiple regression analysis to determinefactors associated with OPG presence or volume in indi-vidual patients (see Additional file 2: Table S2). Thepresence of UBOs (OR = 2.4, 95% CI = 1.2 to 4.8) andthe presence of non-optic gliomas (OR = 4.8, 95% CI = 2.0 to 12) each was associated with the presence of OPGsin a patient. Age at first scan was negatively associatedwith the presence of an OPG (OR = 0.96, 95% CI = 0.96to 0.99). None of the independent variables significantlypredicted tumour volume.Fig. 2 New appearance of an OPG in the left prechiasmatic opticnerve of Patient 8. a No glioma was seen at a scan performed whenpatient was 1.3 years old. No contrast matter was used in this scan.b An avidly enhancing left prechiasmatic optic nerve glioma with avolume of 1820 mm3 was apparent when the patient was 2.0 yearsof age. Both the left eye and the left intraorbital optic nerve werenormal and well visualized in other image planesSellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 5 of 9Fig. 3 Progression of an OPG in Patient 37. a On the first scanperformed at 4.0 years of age, a glioma measuring 1862 mm3 waspresent in the left intraorbital and prechiasmatic optic nerve. b Onthe next scan performed 1.0 years later, the OPG had increased involume to 2636 mm3 and involved the optic chiasm as well as theleft intraorbital and prechiasmatic optic nerveFig. 4 Spontaneous regression of an OPG in Patient 3. a A 516 mm3left prechiasmatic optic nerve glioma on this patient’s first MRI atage 6.3 years. The tumour volume was unchanged over 2 MRIexaminations during the next 2.2 years. b On re-examination at9.3 years of age the OPG volume had decreased to 462 mm3, andthe volume decreased again to 436 mm3 when the patient was11.2 years old. The tumour volume was unchanged on the patient’slast MRI in this study at age 11.7 yearsSellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 6 of 9Because the prevalence of both UBOs and OPGs de-creases with age [11], we investigated the relationshipbetween UBOs and OPGs in individual NF1 patientsafter stratifying patients into 10-year age groups(Table 2). There is a strong overall association betweenthe presence of OPGs and UBOs (Mantel-Haenszel sum-mary odds ratio = 2.77, 95% confidence interval 1.39–5.53, p = 0.0061). This association was also seen in an ana-lysis restricted to 34 patients with asymptomatic OPGs(Mantel-Haenszel summary odds ratio = 3.17, 95% confi-dence interval 1.29–7.80, p = 0.012).DiscussionIn this study we report the largest series of head MRIsdescribed to date in unselected NF1 patients. Most pre-vious studies have used convenience samples to estimatethe prevalence of OPGs in children with NF1 [12, 13].This approach, however, carries the inherent bias of thepatients being selected for having clinical symptoms thatrequired them to undergo imaging. In our study, everypatient seen in the NF outpatient department was of-fered MRI, so our series is an unbiased representation ofthe patients seen in the clinic. Blanchard et al. recentlyperformed a prospective head MRI study of 306 childrenwith NF1 under 6 years of age and found the prevalenceof OPG to be 14.7% (95% confidence interval: 11.0% to19.3%), with 80% of patients being asymptomatic [13].Other authors found similar prevalences in children,ranging from 15%–18% [12, 14, 15]. We found a some-what higher prevalence (22%) among children with NF1under 10 years of age: This might be due to differentdiagnostic criteria (T2 hyperintensity without consider-ation of thickness or tortuosity of the optic nerve) usedin our study compared to the previous studies.The prevalence of OPG in older children and adultswith NF1 is lower than in young children but hasrarely been evaluated. One retrospective study byCréange et al. found the prevalence in 138 individualswith NF1 over 18 years of age to be 5.8% [16]. Inconcordance with this finding, we found the preva-lence in adults over 19.9 years of age to be 4.9% (95%confidence interval: 3.3% to 7.2%).The decline in prevalence of OPG from childhood toadulthood might be explained in several different ways.Firstly, it is important to note that most OPGs areasymptomatic and are never confirmed by biopsy inpeople with NF1 [17, 18]. Optic nerve tortuosity andoptic nerve sheath thickening are frequent in childrenwith NF1 who do not have OPG [19], and it is notknown if T2 hyperintensity or MRI enhancement of theoptic nerves can occur in the absence of other evidenceof neoplasia in this setting. Thus, it is possible that someOPGs diagnosed by MRI in children with NF1 are nottrue neoplasms.Alternatively, there might be increased mortality inindividuals with optic tumours, so that children withOPG are less likely to survive into adulthood. How-ever, a study by Guillamo et al. showed that havingan OPG is not a risk factor for premature death ofNF1 patients [20].It has been shown that having an OPG predisposesto the development of non-optic gliomas [21], whichare associated with increased morbidity [20]. Wefound a strong correlation between presence of OPGand presence of non-optic gliomas: however, this can-not account for the strong decline of OPG prevalencewith increasing age seen in our study, as no patientsdies from non-optic glioma.Lastly, tumours might regress spontaneously, as hasbeen described many times for OPG in case reports ofchildren with NF1 (see Additional file 3: Table S3 and[22–24]). Regression seems to occur mostly in tumoursinvolving the optic chiasm, but may also sometimesoccur in other sections of the optic pathway. In ourstudy, we identified no instances of complete regression ofan OPG but 4 cases of partial regression (see Additionalfile 1: Table S1). All of the patients in this study whoshowed tumour regression were under 20 years of agewhen this occurred. All three of the patients whose MRIsincluded contrast showed avid enhancement before re-gression and mild to no enhancement after regression hadstopped.Among the 17 symptomatic OPG patients, 7 weretreated. Three of these 7 patients (Patients 5, 13 and 17)received chemotherapy soon after symptom onset, andall showed vision improvement after treatment. Of theremaining 4 patients, the age at symptom onset is un-known for 2 patients, 1 patient received surgery and ra-diation followed by a decline in vision, and 1 patientreceived chemotherapy 6 years after symptom onset,Table 2 Frequency (and percentage) of UBOs among NF1 patients with or without OPG by 10-year age groupAge Group OPG Absent Any OPG Present Asymptomatic OPG Present0 to 9.99 years 53/72 (73.6%) 17/18 (94%) 16/17 (94%)10.0 to 19.99 years 57/119 (47.9%) 10/13 (77%) 4/6 (67%)20.0 to 29.99 years 39/109 (35.8%) 3/8 (38%) 3/5 (60%)30.0 to 39.99 years 21/80 (26.3%) 3/8 (38%) 2/5 (40%)40.0 years and above 43/129 (33.3%) 3/4 (75%) 1/1 (100%)Sellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 7 of 9followed by stable vision. This may indicate a benefit tostarting treatment early after symptom onset; however,our sample is too small to show any definitive benefit.Further research is required to investigate whether earlytreatment of symptomatic OPG is beneficial in NF1.Sex has been suggested as a determinant of whichNF1 OPGs become symptomatic. Females were re-ported to receive MRI for visual symptoms signifi-cantly more often than males and were 3 times morelikely to undergo treatment for visual decline in onestudy [25] but not in another [13]. We did not see adifference in tumour location, tumour frequencysymptom status or frequency of treatment initiationbetween males and females.We observed a strong association between the pres-ence of OPG and the presence of UBOs after stratifica-tion by age (Table 2); this association was also seenwhen the analysis was restricted to asymptomatic OPGs.Regression analysis showed a similar association betweenthe presence of OPG and UBOs after adjustment for theeffect of age (Additional file 2: Table S2).There are several parallels between UBOs and asymp-tomatic OPGs: their glial origin, benign nature, usualspontaneous involution, frequent development in earlychildhood and very infrequent development later in life,and decreased prevalence with increasing age. UBOs arethought to be areas of immature myelin or intramyelinicedema [11, 26, 27] and not neoplasms. All studies inves-tigating the histology of OPGs in NF1 patients only in-clude symptomatic patients, as biopsy or surgicalremoval is not performed in asymptomatic patients. Ithas generally been assumed that the pathology (andpathogenesis) of symptomatic and asymptomatic OPGis the same in patients with NF1, but there is no dir-ect evidence supporting this assumption. If manyasymptomatic OPGs are actually areas of immaturemyelin instead of true neoplasms, it will change ourunderstanding of NF1 pathology.Recently, the idea that pediatric gliomas in general areneurodevelopmental disorders has gained traction.Pediatric gliomas vary from their adult counterparts inlocation (posterior fossa and optic pathway in children,supratentorial compartment in adults), their usual type(low-grade pilocytic astrocytoma in children, high-gradeglioblastoma in adults) and their potential for malignanttransformation (low in children, high in adults) [28].OPGs in NF1 patients are often diagnosed in very youngchildren, and few, if any, cases arise in adults. Thisstands in contrast to non-optic gliomas in NF1, whichdo often arise in adults [29, 30].Our study has several limitations. First of all, our studypopulation might not be representative of the NF1 popu-lation as a whole. We cannot rule out referral bias or thepossibility that symptomatic patients are more likely toconsent to participate in an MRI study than asymptomaticpatients. Also, patients with more severe phenotypes arelikely to receive more frequent clinical follow-up and re-peat imaging than patient with less severe manifestations.Another important factor is the diagnosis of OPG basedon imaging. There are no generally-accepted diagnosticguidelines for OPGs in NF1 patients, and diagnosis isbased on clinical judgment.ConclusionThis is the largest prospective study of unselected headand whole-body MRIs ever performed in patients withNF1 [31]. It is also the first study that quantifies the fre-quency of OPG progression and regression. The obser-vations that these lesions are extraordinarily frequent inchildren but are usually asymptomatic and remain sothroughout their course and that many appear to regressspontaneously in late childhood or adolescence supportour current clinical practice of only obtaining frequentfollow-up MRIs in patients who have symptomaticOPGs or tumours that are growing or producing a masseffect. Our data are important for scientists working tounderstand the pathogenesis of NF1-associated lesionsand for clinicians assessing NF1 patients who have OPG.Additional filesAdditional file 1: Table S1. Overview of all 35 asymptomatic OPGpatients. OPG location indicates extent after shrinkage in patients withregression or extent after growth in patients with progression of thetumour. None of the asymptomatic patients received any treatment fortheir OPGs. (DOCX 16 kb)Additional file 2: Table S2. Age-adjusted associations of clinical fea-tures typical for NF1 with the presence of OPG. (XLSX 8 kb)Additional file 3: Table S3. Published cases of spontaneous regressionof symptomatic and asymptomatic OPG in NF1 patients. (XLSX 9 kb)FundingThis study was funded by a grant from the BundesverbandNeurofibromatose e.V.Availability of data and materialsThe dataset supporting the conclusions of this article is included in fullwithin the article.Authors’ contributionsJMF and VFM contributed to the study planning. VFM, SF and RW wereinvolved in image collection and provided clinical patient care. LS, MM,MKSH, PB, JMF and VFM were responsible for data analysis and datavisualization. LS, SF, JMF and VFM were involved in writing and reviewingthe manuscript. All authors read and approved the final manuscript.Ethics approval and consent to participateThe ethical committees of the Medical Chamber in Hamburg and theResearch Ethics Board of the University of British Columbia approved thestudy. Written consent was obtained from all study participants before studybegin. All data were de-identified before analysis.Competing interestsThe authors declare that they have no competing interests.Sellmer et al. Orphanet Journal of Rare Diseases  (2018) 13:62 Page 8 of 9Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Medical Genetics, BC Children’s Hospital, University of BritishColumbia, 4480 Oak Street, Vancouver, Canada. 2Department of Neurology,University Hospital Hamburg-Eppendorf, Hamburg, Germany. 3Diagnosticand Therapeutic Neuroradiology, University of British Columbia, Vancouver,Canada. 4Department of Radiology, MRI Institute Altona, Hamburg, Germany.Received: 5 September 2017 Accepted: 17 April 2018References1. Lammert M, Friedman JM, Kluwe L, Mautner V-F. Prevalence ofneurofibromatosis 1 in German children at elementary school enrollment.Arch Dermatol. 2005;141:71–4.2. Gutmann DH, Collins FS. 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