Spectrum of intracranial manifestations of Neurofibromatosis-1, with specific evaluation of brain...

Spectrum of intracranial manifestations of

Neurofibromatosis-1, with specific evaluation of brain stem

Rakhee Gawande, Russell Pluhm, David NasceneDEPARTMENT OF RADIOLOGY

Control #1632Poster # EP 129

DISCLOSURES

• NONE

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

PURPOSETo 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

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

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.

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 percentageUBO 72 75

Brain stem enlargement 55 57Optic gliomas 44 45

Brain stem glioma 4 4.1Other gliomas 5 5.2Cystic lesions 7 7.3

Non enhancing lesionsat other locations 9 9.3Enhancing lesions 4 4.1

sphenoid wing dysplasia 3 3.1

Comparison of NF1 with controls

Variable CategoryNF1 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

n 95 71 <0.0001


Medulla TR

n 95 72 <0.0001

Median 1.60 1.50 Mean (SD) 1.63 (0.22) 1.49 (0.17)

(Min, Max) (1.20, 2.50) (1.10, 1.80) Pons AP

n 95 72 0.0658


Pons TR

n 95 72 0.0450


Statistically significantdifferences betweenanteroposterior (AP) and transverse (TR)dimensions of medullaand TR dimension of pons between the study and control groups

Comparison of NF1 and control

6 yr old boy with NF1: Note the benign enlargementOf brainstem

6 yr old healthy control: Note normal appearance of the brainstem

LocationAll 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%)

Distribution of NF1 UBOs

Most common location of UBOs was the cerebellum, followedby globus pallidus and medulla.Least common locations were caudate nucleus and putamen

Location Statistics Absent Mild Moderate Severe P-valueGlobus 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 n 103 69 32 9 0.0016 Median 11 8 8.5 7 Mean (SD) 14.10 (11.49) 9.23 (6.05) 8.72 (4.71) 7.11 (2.67) (Min, Max) (0.01, 57.00) (1.00, 26.00) (1.00, 19.00) (3.00, 11.00)

Midbrain n 117 55 25 16 0.0149 Median 11 9 7 7.5 Mean (SD) 13.25 (11.18) 9.82 (6.10) 8.68 (4.92) 7.81 (3.12) (Min, Max) (0.01, 57.00) (1.00, 26.00) (1.00, 19.00) (3.00, 13.00)

Pons n 108 52 30 23 0.0101 Median 11 10 7 7 Mean (SD) 13.07 (11.23) 10.67 (6.44) 8.67 (5.92) 8.91 (6.13) (Min, Max) (0.01, 57.00) (1.00, 30.00) (1.00, 25.00) (3.00, 26.00)

Medulla n 101 59 35 18 0.0014 Median 11 9 7 7 Mean (SD) 13.69 (11.55) 10.46 (6.49) 8.37 (5.41) 7.72 (3.75) (Min, Max) (0.01, 57.00) (1.00, 30.00) (1.00, 25.00) (3.00, 19.00)

Cerebellum n 69 49 58 37 <0.0001 Median 12 11 7 7 Mean (SD) 16.32 (12.33) 11.71 (6.83) 7.76 (5.55) 7.62 (4.85) (Min, Max) (0.01, 57.00) (1.00, 30.00) (1.00, 26.00) (2.00, 25.00)

Association of UBO grade and Age

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.

Analysis Of GEE Parameter Estimates

Empirical Standard Error Estimates

Parameter EstimateStandard

Error95% Confidence

LimitsZ Pr > |Z|

Intercept 16.6206 1.7419 13.2066 20.0346 9.54 <.0001

NUM_SPOT -1.4372 0.3123 -2.0492 -0.8251 -4.6 <.0001

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



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.

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-valuePresence 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) (0.00, 7.00)

At 8 yrs

At 11 yrs

At 15 yrs

Marked, but ultimately benign, nonenhancing enlargement of brainstem

T2 T1 post contrast T1

Brainstem glioma

7 yr old with Juvenile Pilocytic Astrocytoma (JPA)of the medulla. Note large lesion in medulla with cystic and nodular enhancing components

T1W precontrast T1W postcontrast

T2W

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 Yes 11 (84.62) 133 (66.50) 0.8344

No 2 (15.38) 67 (33.50) Caudate Nucleus

Yes 4 (100.00) 140 (66.99) 0.3069

No 0 69 (33.01) Thalamus Yes 79 (71.82) 65 (63.11) 0.6005

No 31 (28.18) 38 (36.89) Midbrain Yes 78 (81.25) 66 (56.41) 0.1324

No 18 (18.75) 51 (43.59) Pons Yes 89 (84.76) 55 (50.93) 0.0034

No 16 (15.24) 53 (49.07) Medulla Yes 98 (87.50) 46 (45.54) <0.0001

No 14 (12.50) 55 (54.46) Cerebellum Yes 112 (77.78) 32 (46.38) 0.0031

No 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

At 7 yrs

At 13 yrs

Decrease in both UBOs and brain stem enlargement with age

Association between presence of brain stem enlargement and optic glioma

Enlargement of brain stem

Variable Category Yes No P-value

Optic Glioma Yes 87 (60.42)

24 (34.78) 0.1657

No 57 (39.58)

45 (65.22)

No statistically significant association between presence of enlargement of brain stem and optic glioma

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

• 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.

SUMMARY

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.

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2. Brainstem lesions in neurofibromatosis type 1. Ullrich NJ, Raja AI, Irons

MB, Kieran MW, Goumnerova L. Neurosurgery. 2007 Oct;61(4):762-6

3. Neurofibromatosis type 1: brain stem tumours. Bilaniuk LT, Molloy PT,

Zimmerman RA, Phillips PC, Vaughan SN, Liu GT, Sutton LN, Needle M.

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