Brain Artery Stenosis in Neurofibromatosis Type 1

(NF1)

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. 2009

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. 2007 Nov 6;116(19):2148-56. 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.

NF1

RasGTP Ras GDP

RafGef

MEK

ERK

CREBP P

RSK

NF1

RasGTP Ras GDP

RafGef

MEK

ERK

CREBP P

RSK

RasGTP Ras GDP

RafGef

MEK

ERK

CREBP P

RSK

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 DIAGNOSIS 8 (10%)

HEADACHES 20 (25%)

VISUAL DEFICIENCY 21 (26%)

ORBITOFACIAL MASS 10 (12%)

MACROCEPHALY 5 (6%)

FOLLOW UP OF KNOWN BRAIN TUMOR 4 (5%)

DEVELOPMENT DELAY 10 (12%)

PONTINE SIGNS 1 (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.

Gender Age at Neuroimaging

MRI Vascular Findings

1 M 22 Stenosis: left ICA

2 F 35 Stenosis: left MCA; right ACA. Narrowing left ICA

3 F 10 Stenosis: right ICA, right MCA, right PCA, and both the ACA’s

4 F 4 Stenosis: left MCA

5 M 12 Stenosis: supraclinoid ICA, right PCA (Moyamoya)

6 M 19 Stenosis: right PCA

7 F 21 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 - 0.5 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-1.5 T MRI-MRA (TOF 3D)

-Gender: F-Age: 10y-1.5 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), 20:382-391

Localization of the stenoses, outside of

the irradiated field for the right optic nerve,

not excluding a neurofibromatosis

cause!

-Gender: F-Age: 4y-1.5 T MRI-MRA (TOF 3D)

Stenosis left MCA and rigth PCA

-Gender: M-Age: 12 y-1.5 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-1.5 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.

-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

Service of Neuroradiology University Federico II Neaples