Brain Artery Stenosis in Neurofibromatosis Type 1 (NF1) A. D’Amico, F. D’Arco, F. Caranci, D. Melis, R. Taurisano,E. Del Giudice, G. Lama, A. Scuotto, R. Conforti, M. Melone, N. Di Paolo, A. Brunetti.

In addition to the most frequently encountered abnormalities such as café au lait spots, nerve sheath tumors, low grade gliomas, the protein product of the NF1 gene ( neurofibromin ) expressed in endothelial and smooth muscle cells, could be responsible for a NF1 associated vasculopathy.

“ The prevalence of cerebral arteriopathy in children with NF1 is at least 6% and was associated with young age and optic glioma” Rea et al Neurofibromin product by the NF1 gene is an ubiquitary protein, that interacts with RAS “Nf1 regulation of RAS plays a critical role in vascular smooth muscle proliferation” * Xu et al. *Circulation Nov 6;116(19): Epub 2007 Oct 22.NF1 regulates a Ras- dependent vascular smooth muscle proliferative injury response.Xu J, Ismat FA, Wang T, Yang J, Epstein JA.

Regulation by NF1 on RAS pathway endothelial and smooth muscle cells proliferation NF1 associated vasculopaty

- 81 patients with NF1 (diagnosed according to standard criteria NIH) - 62 studies performed by using a 1.5 T magnet (Intera Philips) MRI + MRA: axial SE T1w, axial TSE T2w, axial and coronal FLAIR T2w, DWI/ADC, coronal STIR, T1w Gd + (when an orbital, a brain or a spine neoplasm was suspected ), 3D TOF MRA (for vessel imaging and stenoses research ) - 19 studies perfomed by using a 0.5 magnet (Vectra GE medical System) MRI : axial, coronal, sagittal GE T1w, axial SE-PD/T2w. MRA (2D TOF) was performed in only 2 patients

“… the NIH Consensus Developement Conference did not recommend CT or MRI studies for asyimptomatic patients with NF1…” 1 1 “… perform cranial MRI only in patiens in whom there is a clinical indication, such a visual or endocrine disturbance, increasing occipitofrontal circumference, headache suggestive of intracranial pathology, seizures and follow up of intracranial and spinal tumors…” 2 2 SYMPTOMS N (%) NEW NF1 DIAGNOSIS8 (10%) HEADACHES20 (25%) VISUAL DEFICIENCY21 (26%) ORBITOFACIAL MASS10 (12%) MACROCEPHALY5 (6%) FOLLOW UP OF KNOWN BRAIN TUMOR4 (5%) DEVELOPMENT DELAY10 (12%) PONTINE SIGNS1 (1%) SUSPECT PARAMEDIAN DIENCEPHALIC SYNDROME 1 (1%)

Multiple intracranial arterial stenoses were found in 6 patients (7%): -3 females, 3 males -Age range: 4-35 / mean: 14,83 -All patients had no clinical signs of cerebral vasculopaty A patient with a large fusiform intracavernous aneurysm of the left ICA and a second controlateral smaller aneurysm Sudden left painful ophthalmoplegia caused by aneurysm thrombosis Underwent a Brain Angiography

Patient No. GenderAge at Neuroimaging MRI Vascular Findings 1 M 22 Stenosis: left ICA (0.5 T 2D TOF MRA) 2F35 Stenosis: left MCA; right ACA. Narrowing left ICA 3F10 Stenosis: right ICA, right MCA, right PCA, and both the ACA’s 4F4 Stenosis: left MCA 5M12 Stenosis: supraclinoid ICA, right PCA (Moyamoya) 6M19 Stenosis: right PCA 7F21 Intracavernous aneurysm of left (++) and right (+) ICA’s

Advanced stenosis of the entire intracranial tract of the left internal carotid artery ( ICA ) - Gender: M - Age 22 y T 2D-TOF MRA

Important narrowing of left carotid siphon Flow signal of the left MCA and right ACA was not appreciable - Gender: F - Age: 35y T MRI-MRA (TOF 3D)

- Gender: F - Age: 10y T MRI-MRA (TOF 3D) Previously treated by radiotherapy consequently to a right optic nerve glioma. Cavernous malformation of the left temporal lobe

Advanced stenosis of the entire tract of the right ICA with absence of flow signal from the right MCA, and both the ACA’s and focal stenosis of the right PCA

“…especially for children with optic gliomas treated with radiotherapy, whereby about 30% of the cases experience a progressive vascular pathology… within the field of irradiation…” Childs Nerv Syst (2004), 20: Localization of the stenoses, outside of the irradiated field for the right optic nerve, not excluding a neurofibromatosis cause!

- Gender: F - Age: 4y T MRI-MRA (TOF 3D) Stenosis left MCA and rigth PCA

- Gender: M - Age: 12 y T MRI-MRA (TOF 3D)/CE-MRI Complete bilateral disappearing of the supraclinoid ICA and of the right PCA, with a lot of secondary vessels collateralizations, delineating a typical case of Moyamoya (“puff of smoke”).

- Gender: M - Age: 19 y T MRI-MRA (TOF 3D) Stenosis of the right PCA

- Gender: M - Age: 21 y - Angio-CT - Angiography Large fusiform intracavernous aneurysm of the left ICA BECAME SYMPTOMATIC:left painful ophthalmoplegia caused by aneurysm thrombosis. BECAME SYMPTOMATIC:left painful ophthalmoplegia caused by aneurysm thrombosis.

- Prevalence of cerebral arteriopathy in this study was about 7% - Real prevalence of cerebral arteriopathy could be understimated because majority of patients are asymptomatic or don’t undergo an MRA - About 30% of patients have a progressive vessel stenosis and symptoms worsening - Association with optic glioma has been described  possible BIAS: Patients with glioma undergo brain MRI

To be… or not to be… Actual guidelines: perform MRI only in patients in whom there is clinical indication MRA increase time of an MRI-brain exam by about 12% (Rea et al. 2009) NF1 patients who are undergoing neuroimaging should have MRA for detect arteriopathy that may be progressive and asymptomatic MRI MRI-MRA indication to revascularization % Arteriopathy detected time€

Service of Neuroradiology University Federico II Neaples