1. Control #1632
Poster # EP 129
Spectrum of intracranial manifestations of Neurofibromatosis-1, with specific evaluation of brain stem
Rakhee Gawande, Russell Pluhm, David Nascene
DEPARTMENT OF RADIOLOGY

2. DISCLOSURES
NONE

3. INTRODUCTION Neurofibromatosis-1 (NF1)
Most common inherited autosomal dominant genetic disorder
Affects one in 3000 live births
Multiple intra-cranial manifestations
Most common associated tumor: Optic glioma (15%)
Benign nonenhancing T2 hyperintense lesion called unidentified bright objects (UBO) frequently seen
UBOs are reportedly found in 43-97% patients
UBOs more common in children and evolve over time
UBOs believed to correspond to areas of vacuolar or spongiotic change
UBOs located in the brainstem may be associated with benign enlargement or brain stem and may be difficult to distinguish from low grade neoplasm

4. PURPOSE
To determine:
Any difference in the AP and transverse measurements of pons and medulla between NF-1 and control groups
Any correlation between age and presence/grade of UBOs
Any correlation between number of UBOs and presence of brain stem enlargement
Any correlation between presence of optic glioma and brain stem enlargement

5. MATERIAL AND METHODS
Retrospective review of brain MRI of patients with NF-1.
Location of UBO divided into 8 areas: globus pallidus, putamen, caudate nucleus, thalamus, midbrain, pons, medulla and cerebellum.
Lesions graded on a 3 point scale absent, mild (grade 1), moderate (grade 2) and severe (grade 3).
Presence of brain stem enlargement noted qualitatively
AP and TR dimensions of pons and medulla measured in control and study group
Additional lesions recorded as optic gliomas, other gliomas, nonenhancing lesions, enhancing lesions and cystic lesions.
Following sequences evaluated: Sagittal T1, axial T2 and FLAIR and postcontrast T1-weighted in multiple planes

6. STATISTICAL ANALYSIS
Comparison between NF-1 patients and controls: p-value is calculated from two sample t-test for continuous variables, and fisher’s exact test for categorical variables.
Association between age and grade of UBO’s: Age is summarized by grade of each NF-1 spot, and p-value is calculated by generalized estimating equation (GEE) to account for within-subject correlation
Association between presence of brain stem enlargement and location of UBO’s: Presence of brain stem enlargement is summarized by presence of each NF-1 spots, and p-value is calculated by generalized estimating equation (GEE) to account for within-subject correlation
Association between presence of optic glioma and brain stem enlargemen: P-value is from logistic regression with generalized estimating equation (GEE) to account for within-subject correlation. Presence of optic glioma is the dependent variable, and presence of bulky brain stem is used as independent variable.

7. RESULTS
Review of database revealed 264 patients with a diagnosis of NF-1.
Brain MRI available in 96 subjects
A total of 213 MRI of 96 subjects were evaluated
Follow up imaging available in 62 subjects
72 age matched control MRI were included to compare brain stem dimensions
Pathology N
percentage
UBO 72 75
Brain stem enlargement 55 57
Optic gliomas 44 45
Brain stem glioma 4
4.1
Other gliomas 5
5.2
Cystic lesions 7
7.3
Non enhancing lesions
at other locations 9
9.3
Enhancing lesions
sphenoid wing dysplasia 3
3.1

8. Comparison of NF1 with controls
Variable
Category
NF1 Patient (N=96)
Control (N=72)
P-value
Sex
Male
41 (42.71)
31 (43.06)
Female
55 (57.29)
41 (56.94)
Age n 96 72
Median
7.50
14.50
Mean (SD)
10.54 (10.67)
17.43 (15.84)
(Min, Max)
(0.01, 57.00)
(1.00, 58.00)
Medulla AP 95 71
<0.0001
1.10
1.17 (0.18)
1.04 (0.13)
(0.80, 1.90)
(0.70, 1.40)
Medulla TR
1.60
1.50
1.63 (0.22)
1.49 (0.17)
(1.20, 2.50)
(1.10, 1.80)
Pons AP
0.0658
2.00
2.05
2.06 (0.27)
1.97 (0.32)
(1.20, 2.90)
(1.20, 2.60)
Pons TR
0.0450
2.70
2.73 (0.31)
2.62 (0.38)
(2.10, 3.70)
(1.60, 3.20)
Statistically significant
differences between
anteroposterior (AP)
and transverse (TR)
dimensions of medulla
and TR dimension of
pons between the
study and control
groups

9. Comparison of NF1 and control
6 yr old boy with NF1: Note the benign enlargement
Of brainstem
6 yr old healthy control: Note normal appearance of the brainstem

10. All records from NF1 Patient
Distribution of NF1 UBOs
Location
All records from NF1 Patient
(N=213)
Globus Pallidus
130 (61.03%)
Putamen
13 (6.10%)
Caudate Nucleus
4 (1.88%)
Thalamus
110 (51.64%)
Midbrain
96 (45.07%)
Pons
105 (49.30%)
Medulla
112 (52.58%)
Cerebellum
144 (67.61%)
Most common location of UBOs was the cerebellum, followed
by globus pallidus and medulla.
Least common locations were caudate nucleus and putamen

11. Association of UBO grade and Age
Location
Statistics
Absent
Mild
Moderate
Severe
P-value
Globus Pallidus n 83 62 45 23
0.0002
Median 12
9.5 8 7
Mean (SD)
15.54 (12.11)
9.85 (6.57)
8.29 (4.51)
6.87 (2.36)
(Min, Max)
(0.01, 57.00)
(1.00, 26.00)
(1.00, 18.00)
(1.00, 11.00)
Thalamus
103 69 32 9
0.0016 11
8.5
14.10 (11.49)
9.23 (6.05)
8.72 (4.71)
7.11 (2.67)
(1.00, 19.00)
(3.00, 11.00)
Midbrain
117 55 25 16
0.0149
7.5
13.25 (11.18)
9.82 (6.10)
8.68 (4.92)
7.81 (3.12)
(3.00, 13.00)
Pons
108 52 30
0.0101 10
13.07 (11.23)
10.67 (6.44)
8.67 (5.92)
8.91 (6.13)
(1.00, 30.00)
(1.00, 25.00)
(3.00, 26.00)
Medulla
101 59 35 18
0.0014
13.69 (11.55)
10.46 (6.49)
8.37 (5.41)
7.72 (3.75)
(3.00, 19.00)
Cerebellum 49 58 37
<0.0001
16.32 (12.33)
11.71 (6.83)
7.76 (5.55)
7.62 (4.85)
(2.00, 25.00)
Increasing severity of UBOs was associated with younger age. Follow-up imaging on
several subjects showed decreasing T2 hyperintensities with age. Also the NF-1 spots
appeared to evolve with time and had different appearance on follow-up imaging.

12. Analysis Of GEE Parameter Estimates Empirical Standard Error Estimates
Association of UBO grade and Age
Analysis Of GEE Parameter Estimates
Empirical Standard Error Estimates
Parameter
Estimate
Standard Error
95% Confidence Limits Z
Pr > |Z|
Intercept
1.7419
9.54
<.0001
NUM_SPOT
0.3123
-4.6
Association between age and number of UBOs. Linear regression with generalized estimating equation (GEE) is used to account for within-subject correlation. Age is the dependent variable, and number of UBO is the independent variable.
Increased number of UBOs is associated with younger age

13. Association of UBO grade and Age
9 yr old
14 yr old
17 yr old
Serial Follow-up images of a subject with NF-1. Note decreasing size and intensity of UBO’s with age.

14. Enlargement of Brain Stem
BENIGN BRAINSTEM ENLARGEMENT
Benign enlargement of brain stem present in 55 patients (57%)
Statistically significant correlation between presence of UBO and enlargement of brain stem.
Enlargement of Brain Stem
Category
Yes No
P-value
Presence of UBO n
144 69
0.0256
Median 5 2
Mean (SD)
3.94 (2.28)
2.13 (2.15)
(Min, Max)
(0.00, 7.00)

15. Marked, but ultimately benign, nonenhancing enlargement of brainstem
At 8 yrs
At 11 yrs
At 15 yrs T2
T1 post contrast T1

16. 7 yr old with Juvenile Pilocytic Astrocytoma (JPA)
Brainstem glioma
T2W
T1W precontrast
T1W postcontrast
7 yr old with Juvenile Pilocytic Astrocytoma (JPA)
of the medulla. Note large lesion in medulla with cystic and
nodular enhancing components

17. Association of location of UBOs with presence of brainstem enlargement
Presence of UBO
Location
Brainstem Enlargement
Present
Absent
P-value
Globus Pallidus
Yes
96 (73.85)
48 (57.83)
0.9149 No
34 (26.15)
35 (42.17)
Putamen
11 (84.62)
133 (66.50)
0.8344
2 (15.38)
67 (33.50)
Caudate Nucleus
4 (100.00)
140 (66.99)
0.3069
69 (33.01)
Thalamus
79 (71.82)
65 (63.11)
0.6005
31 (28.18)
38 (36.89)
Midbrain
78 (81.25)
66 (56.41)
0.1324
18 (18.75)
51 (43.59)
Pons
89 (84.76)
55 (50.93)
0.0034
16 (15.24)
53 (49.07)
Medulla
98 (87.50)
46 (45.54)
<0.0001
14 (12.50)
55 (54.46)
Cerebellum
112 (77.78)
32 (46.38)
0.0031
32 (22.22)
37 (53.62)
Statistically significant correlation was found between presence of UBOs in the pons, medulla, and cerebellum and presence of benign brain stem enlargement

18. At 7 yrs
At 13 yrs
Decrease in both UBOs and brain stem enlargement with age

19. Enlargement of brain stem
Association between presence of brain stem enlargement and optic glioma
Enlargement of brain stem
Variable
Category
Yes No
P-value
Optic Glioma
87 (60.42)
24 (34.78)
0.1657
57 (39.58)
45 (65.22)
No statistically significant association between presence of enlargement of brain stem and optic glioma

20. SUMMARY
Statistically significant differences between AP and TR dimensions of medulla and TR dimension of pons between NF1 and controls.
Benign enlargement of brain stem present in 57%
Statistically significant correlation between presence of UBO and enlargement of brain stem.
Statistically significant correlation between location of UBO in cerebellum, pons and medulla and enlargement of brain stem
No statistically significant association between presence of enlargement of brain stem and optic glioma

21. SUMMARY
Most common location of UBOs was the cerebellum, followed by globus pallidus and medulla.
Least common locations were caudate nucleus and putamen
Increased severity of UBOs was associated with younger age.
Follow-up imaging on several subjects showed decrease in both UBOs and brain stem enlargement over time.

22. CONCLUSION
Non enhancing T2 hyperintense lesions (UBO’s) are commonly seen in the cerebellum and brain stem in patients with NF-1.
Associated brain stem enlargement is frequently seen and should not be mis-interpreted as brain stem neoplastic process.

23. REFERENCES
1. Diffuse pontine lesions in children with neurofibromatosis type 1: making a case for unidentified bright objects. Hervey-Jumper SL, Singla N, Gebarski SS, Robertson P, Maher CO. Pediatr Neurosurg. 2013;49(1): Brainstem lesions in neurofibromatosis type 1. Ullrich NJ, Raja AI, Irons MB, Kieran MW, Goumnerova L. Neurosurgery Oct;61(4): Neurofibromatosis type 1: brain stem tumours. Bilaniuk LT, Molloy PT, Zimmerman RA, Phillips PC, Vaughan SN, Liu GT, Sutton LN, Needle M. Neuroradiology Sep;39(9): Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Broniscer A, Gajjar A, Bhargava R, Langston JW, Heideman R, Jones D, Kun LE, Taylor J. Neurosurgery Feb;40(2):331-7