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Original Research |
1 Department of Radiology, Division of Nuclear Medicine, St. Louis University
Hospital, 3635 Vista Ave. at S Grand Blvd., St. Louis, MO 63110.
2 Department of Radiology, St. Louis University Hospital, St. Louis, MO.
3 Present address: Nuclear Medicine Unit, Assuit University Hospital, Assuit,
Egypt.
4 Cancer Center, St. Louis University, St. Louis, MO.
Received December 14, 2007;
accepted after revision June 13, 2008.
Address correspondence to N. C. Nguyen
(nguyenn{at}slu.edu).
Abstract
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MATERIALS AND METHODS. Fifteen healthy volunteers and 35 patients with lung carcinoma—14 without brain metastasis and 21 with brain metastases—were retrospectively studied. The individuals underwent whole-body PET/CT including the brain with low-dose and unenhanced CT. Two nuclear medicine physicians visually analyzed the posterior ocular bulb uptake of both eyes. Standardized uptake values (SUVs) in the posterior ocular bulb were compared among the study groups. A radiologist reviewed brain MRI scans for abnormalities in the ocular bulbs and orbits.
RESULTS. Visual interpretation showed normal FDG uptake at the
posterior ocular bulb in 14 of the 15 healthy volunteers and 12 of the 14
(86%) patients without brain metastasis. Seventeen of the 21 (81%) patients
with brain metastases showed increased uptake in the posterior ocular bulb.
Visual interpretation showed no statistically significant difference between
the healthy volunteers and patients without brain metastasis (p =
0.671). However, there was a significant difference between the patients with
brain metastases and healthy volunteers as well as patients without brain
metastasis (both, p < 0.001). High interrater agreement (
=
0.83) was noted. Brain MRI showed no abnormalities at the posterior ocular
bulb in all study subjects. SUV results were inaccurate because of the intense
tracer activity in the posterior orbit nearby. A good correlation between
visually increased posterior ocular bulb uptake and the presence of brain
metastasis was present (Cramer's V = 0.61).
CONCLUSION. Visually increased FDG uptake along the posterior ocular bulb is an abnormal finding and may indicate intracranial structural abnormalities such as brain metastases.
Keywords: brain metastasis • ocular bulb • oncologic imaging • 18F-FDG • whole-body PET/CT
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In oncology, whole-body PET/CT is typically performed from the skull base to the pelvic floor because most FDG-avid lesions are expected to be in this field of view except cerebral metastasis, which can be found in approximately 20% of cancer patients during their lifetime [3]. In our PET center, the brain is routinely imaged with the cost of one additional field of view that allows detection of previously unsuspected brain metastasis. We observed that PET/CT of several patients with brain metastasis showed increased FDG uptake at the posterior ocular bulb, and therefore we suspected a relationship between the cerebral metastasis and increased tracer distribution at the posterior ocular bulb. We hypothesized that increased posterior ocular bulb activity is abnormal and may indicate brain metastases. To clarify this hypothesis, we studied a group of healthy volunteers and two patient groups, one with and the other without brain metastasis. To our best knowledge, FDG uptake in the posterior ocular bulb has never been described and its role in detecting intracranial metastasis has never been discussed in the literature.
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The institutional review board approved this retrospective study.
PET/CT
The volunteers and patients fasted at least 4 hours before the PET/CT
examination and received an IV injection of approximately 5.18 MBq/kg of body
weight (0.14 mCi/kg) of FDG, with a maximum dose of 444 MBq (12 mCi). Blood
glucose concentration was < 200 mg/dL immediately before tracer injection
in all study subjects. Study subjects sat in a quiet room where the injection
was performed and were instructed not to talk during the subsequent
45–60 minutes of the FDG uptake phase. All scans were acquired during
normal breathing on a PET/CT scanner (Gemini, Philips Healthcare) using an
axial coscan range of 193 cm that enabled head-to-toe (true whole-body)
imaging in one sweep. Dedicated PET of the brain was not performed. The study
subjects were not given any specific instructions about whether to open or
close their eyes during PET/CT scanning.
CT
The PET/CT scanner consisted of a 16-MDCT unit, and CT was performed before
PET. The parameters were as follows: 120–140 kV and 33–100 mAs,
0.5 second per CT rotation, pitch of 0.9, and 512 x 512 matrix. CT data
were used for image fusion and the generation of the CT transmission map.
Neither oral nor IV contrast material was used.
PET
Emission data were acquired for 18–22 bed positions. Emission scans
were acquired at 3 minutes per bed position with a 50% overlap. The 3D
acquisition parameters consisted of a 128 x 128 matrix and an 18-cm
field of view. Processing consisted of the 3D row action maximum likelihood
algorithm (RAMLA) method
[4].
Brain MRI
MRI was performed on a 1.5-T scanner (Intera, Philips Healthcare) with a
head coil. Imaging sequences included transverse unenhanced and enhanced
T1-weighted fast spin-echo images (TR/TE, 580/20); T2-weighted images
(6,300/110) in the axial, coronal, and sagittal planes; and FLAIR (6,000/120)
and diffusion-weighted images in the axial plane. The MR contrast agent was
gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma), which was given
IV in a dose of 0.1 mmol/kg.
Image Analysis
The PET/CT images were evaluated on a workstation (Syntegra, Philips
Healthcare). Two nuclear medicine physicians blinded to clinical data visually
analyzed the posterior ocular bulb tracer activity.
FDG uptake in the posterior ocular bulb was determined as normal (negative) if there was no noticeable tracer activity in the posterior ocular bulb and as abnormal (positive) if tracer activity in the posterior ocular bulb was noticed; in the latter cases, the degree of FDG increase was graded as either mild or prominent. The CT portion of PET/CT delineates well the posterior ocular bulb from the remaining soft tissues in the eyes. Thus, this intrinsic PET/CT registration eliminates the need for a separate coregistration of PET and MRI. The mean standardized uptake value (SUV) was obtained after manually drawing a region of interest along the central aspect of the posterior ocular bulb.
Brain MRI studies acquired at our institution were reviewed retrospectively by a radiologist with expertise in MRI for the detection of abnormalities in the ocular bulbs and orbits. MRI findings regarding lesion size, mass effect, midline shift, and vasogenic edema were also collected.
Statistical Analysis
Patient characteristics were assessed using measures of central tendency
(mean ± SD) and frequencies (%) for categoric variables. Independent
Student's t tests were used to compare the findings of mean SUV,
Wilcoxon's tests to compare the mean SUV in the same study subjects, Fisher's
exact tests to compare the findings of visual interpretation, and the value of
Cramer's V to correlate the findings of posterior ocular bulb uptake with the
presence of brain metastasis. Interrater agreement () was used to
evaluate the degree of agreement between the two readers. Associations or
differences were defined as statistically significant when alpha was <
0.05. Statistics software (MedCalc software version 9.3.0.0, MedCalc) was
used.
Medical Records
The patients' medical records regarding tumor cell type, neurologic and
ophthalmologic symptoms, risk factors for retinopathy such as hypertension and
diabetes mellitus as well as treatment modalities and surgical interventions
of the brain were evaluated by the two nuclear medicine physician readers
after interpretation of posterior ocular bulb activity was completed. In
addition, results of WBC counts in the patient group with brain metastases
were included.
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Interrater agreement between the two nuclear medicine readers was good
( = 0.83). There was a good correlation between increased posterior
ocular bulb uptake and the presence of brain metastasis (Cramer's V = 0.61).
The corresponding sensitivity, specificity, positive predictive value, and
negative predictive value were 61.9%, 94.9%, 74.4%, and 91.2%, respectively.
False-positive posterior ocular bulb uptake was noted in two patients without
brain metastasis and one healthy volunteer. The degree of positive posterior
ocular bulb uptake was mild in 17 of 25 (68%) eyes and prominent in eight of
25 (32%) eyes, in which both readers agreed about the positive ocular bulb
findings. Most patients and healthy volunteers had intense FDG activity in the
posterior orbits that corresponded to nearby ocular muscles. Prominent FDG
activity in the anterior ocular bulbs was found in all 15 healthy volunteers
and 35 cancer patients.
On a per-patient basis, PET/CT scans identified FDG-avid metastatic brain lesions in 19 of the 21 patients with brain metastases (sensitivity = 90%); no FDG-avid lesions were noted in two (10%) patients. Positive posterior ocular bulb uptake was present in one patient, who had bilateral infra- and supratentorial lesions measuring up to 2.1 cm (Figs. 2A, 2B, 2C, 2D, 2E, and 2F). No increased posterior ocular bulb uptake was present in the other patient, who had bilateral supratentorial lesions measuring up to 1 cm.
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Semiquantitative Evaluation
The difference in mean SUVs was not statistically significant between the
patients with bilateral increased posterior ocular bulb uptake and the healthy
volunteers without increased posterior ocular bulb uptake (1.3 ± 0.3 vs
1.2 ± 0.3, respectively; p = 0.844). Also, the mean SUV of the
side with positive posterior ocular bulb uptake compared with that of the
contralateral negative side (Figs.
3A,
3B,
3C, and
3D) was not statistically
significantly different (1.3 ± 0.3 vs 1.4 ± 0.5; p =
0.813).
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All four patients (24%) without neurologic symptoms by the time they underwent PET/CT were found to have increased posterior ocular bulb uptake bilaterally. One patient (6%) presenting with dizziness and disorientation was found to have bilateral asymptomatic papilledema and a 1.5-cm intraaxial enhancing lesion in the right posterior parietal lobe that was associated with moderate vasogenic edema as seen by brain MRI, but neither mass effect nor midline shift was present. Table 2 summarizes the distribution of posterior ocular bulb uptake in the patients with brain metastases.
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WBC counts were increased, measuring up to 14,000/µL (normal range, 3,400–10,500/µL), in three of the 18 patients with brain metastases. A comparison of the clinical data of patients without brain metastasis and those with brain metastases is shown in Table 3.
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Overall, visually increased FDG uptake in the posterior ocular bulb can be considered abnormal. The SUV did not contribute to the detection of visually positive posterior ocular bulb uptake because the intense FDG activity in the neighboring posterior orbits limited accurate measurement of SUV. Our findings showed that positive posterior ocular bulb findings—as present in 17 of the 21 (81%) patients with brain metastases—correlated well with the presence of brain metastasis (Cramer's V = 0.61).
Paraneoplastic disorders may affect the eyes. Cancer-associated retinopathy is the most common of the paraneoplastic disorders usually causing visual loss [7, 8]. Some patients, perhaps a subset of patients with cancer-associated retinopathy, have pure cone dysfunction [9, 10]. Among the 21 patients with brain metastases, one presented with bilateral increased posterior ocular bulb uptake and frequent falls, near syncopes, as well as pain and blurriness in the right eye; this patient had an ipsilateral 3.4 x 2.4 cm mass in the right temporal lobe that had caused midline shift and significant vasogenic edema. Another patient showed increased posterior ocular bulb uptake on the right and complained of visual hallucination, right-sided headache, and left upper arm paresis; this patient had an ipsilateral 1.0-cm metastatic lesion in the right parietooccipital lobe with significant vasogenic edema. However, given the matched neurologic symptoms and positive posterior ocular bulb uptake, the eye symptoms in these two patients likely resulted from the brain lesions and were unlikely related to paraneoplastic disorders. Clinically, paraneoplastic disorders as a cause of increased posterior ocular bulb uptake were unlikely because of absent eye symptoms in most patients with brain metastases (89%) and in all patients without brain metastasis.
A relationship between increased posterior ocular bulb uptake and possible choroidal metastasis was also unlikely because its prevalence in patients with disseminated lung carcinoma is very low (2%) [11], which is in contrast to the high prevalence (81%) of increased posterior ocular bulb uptake in the studied patients with brain metastases.
Arterial hypertension, diabetes mellitus, or both were encountered in both patient groups, more so in the patients without brain metastasis (7/13 = 54%) than in the patients with brain metastases (9/18 = 50%). Because of the almost equal distributions of these medical conditions between the patients with brain metastases and those without brain metastasis and the disparity of posterior ocular bulb uptake between the same groups, arterial hypertension and diabetes are unlikely to be the cause of increased posterior ocular bulb uptake. Chemotherapeutic agents used in lung cancer treatment are known to cause neurotoxicities [12]; however, ocular toxicities such as retinopathy and choroidopathy have not been described in the literature to our knowledge. Our findings did not support a correlation between increased posterior ocular bulb uptake and chemotherapy because the low percentage of patients with brain metastases undergoing chemotherapy (4/21 = 19%) did not match the high prevalence of increased posterior ocular bulb uptake (81%).
Direct tumor invasion of the eyes can be excluded in all studied patients because MRI of the brain showed no tumor involvement of the orbits and oculi. Radiation retinopathy may occur after radiation treatment to the orbit or the adjacent structures in the brain [13]. Because of the small number of patients with brain metastases who had a recent history of radiation therapy to the brain (4/21 = 19%) and the unmatched high frequency of increased posterior ocular bulb uptake in this patient group (81%), a radiation-induced retinopathy was unlikely. Three of the 21 (14%) patients with brain metastases underwent surgical intervention to the brain within 3 months before the PET/CT study. There was no clinical suspicion for an infectious process also because only three of the 18 (17%) patients with brain metastases had increased WBC counts.
The pathophysiology of increased posterior ocular bulb uptake as detected by FDG PET/CT is unknown and has yet to be investigated. A plausible explanation of the posterior ocular bulb activity relates to blood stasis that is caused by increased pressure in the subarachnoid space. Increased pressure in the subarachnoid space can cause compression of the central vein of the retina and thereby can cause stasis of venous return and impede lymphatic drainage from the retinal and optic nerve [14]. This may be the cause of increased posterior ocular bulb uptake.
Of note, one patient with brain metastases had a history of bilateral papilledema. CSF must pass through the narrow meshes of the arachnoid trabecular meshwork to reach the orbital part of the sheath. Increased pressure in the subarachnoid space is usually seen bilaterally because there is communication between the subarachnoid space of the optic nerve and that of brain [14, 15]. Similarly, bilateral increased posterior ocular bulb activity was present in 11 of 17 (65%) patients with brain metastases. The various degrees of communication can result in different degrees of papilledema and may explain the different degrees of increased posterior ocular bulb uptake—mild in 17 of 25 (68%) patients and prominent in eight of 25 (32%) [14]. Moreover, not all intracranial tumors will cause papilledema [16], and not all brain metastases will cause increased posterior ocular bulb activity, as was the case in four of the 21 patients with brain metastases in our study. Lepore [17] found that the degree of subarachnoid communication at the chiasma affects the symmetry of papilledema. An analogous finding is that 10 of 12 patients with one-sided brain metastasis presented with increased posterior ocular bulb uptake that was symmetric in seven and asymmetric in three. These findings may support our theory of a mechanism induced by increased pressure in the subarachnoid space.
Probably the best explanation of increased posterior ocular bulb uptake is made up of both blood stasis and FDG hypermetabolism. Hypothetically, subtle pressure changes in the subarachnoid space may result in stasis of venous return and impede lymphatic drainage, resulting in a relative oxygen deficit at the posterior ocular bulb that then may trigger FDG hypermetabolism. Researchers have shown that hypoxia can induce increased FDG uptake in living tissue [18]. However, further evaluation is needed to prove this theory.
Rohren et al. [1] found the sensitivity and specificity of FDG PET for the detection of cerebral metastases to be 75% and 83%, respectively, on a per-patient basis. They noted, however, that the sensitivity decreased to 61% on a per-lesion basis, which is a major limitation of FDG PET in diagnosing brain metastasis. Given the moderate positive predictive value of 74.4% and the high negative predictive value of 91.2%, a positive posterior ocular bulb finding may have added value in diagnosing brain metastases. A combined reading to identify both intraparenchymal brain lesions and abnormal posterior ocular bulb uptake may complement each other. In this regard, the evaluation of posterior ocular bulb uptake helped diagnose brain metastasis in one of the 21 (5%) patients with brain metastases that was not detected by visual assessment of the brain parenchyma alone; this patient presented with asymptomatic bilateral brain lesions that were missed because of low FDG avidity. On the other hand, the use of posterior ocular bulb uptake alone missed four patients who had FDG-avid brain metastases. Visually increased posterior ocular bulb uptake can be an indirect sign of brain metastasis. This finding is, however, not specific for brain metastasis because it can be found, for example, in patients with complex partial seizure (Nguyen et al., unpublished data). However, in a patient with a history of cancer and no history of brain disorders, increased posterior ocular bulb uptake may be suggestive of brain metastasis.
The goal of this pilot study was to show that increased posterior ocular bulb uptake possibly has value for diagnosing brain metastasis. Therefore, we did not compare the diagnostic accuracy of increased posterior ocular bulb uptake with that of FDG-avid brain lesions. For optimal detection of brain lesions, a dedicated brain imaging protocol of at least 10 minutes—instead of 3 minutes per bed position as performed in this study—is desirable. In the current study, a 3-minute bed position appears sufficient for the detection of both FDG-avid lesions, with a sensitivity of 90% on a per-patient basis, and abnormal posterior ocular bulb uptake. Currently, the standard imaging protocol for FDG PET/CT is from the basal skull to the upper thigh. With this imaging protocol, the ocular bulbs are often incompletely imaged, which would limit assessment of posterior ocular bulb uptake. If the eyes, however, are fully seen on available images and are free of image artifacts, increased posterior ocular bulb uptake may indicate the presence of brain metastasis and warrant an evaluation of the brain with contrast-enhanced MRI irrespective of the findings in the visible portions of the brain. This strategy is supported by the fact that four of the 17 (24%) patients with brain metastases with positive posterior ocular bulb uptake had no neurologic symptoms at the time of PET/CT. These abnormal posterior ocular bulb findings would have prompted MRI of the brain and helped diagnose previously unsuspected brain metastases.
We believe that including the whole brain in the imaging protocol may be justified because published data about the detection of brain metastasis were based on FDG PET alone [1, 2]. The intrinsic registration of PET/CT, particularly with contrast enhancement, however, may increase the diagnostic accuracy and the utilization of PET/CT for brain metastasis screening. In addition, the presumed increased diagnostic accuracy of combined assessment of FDG-avid brain lesions and increased posterior ocular bulb uptake may further improve the detection of brain metastasis. We believe that patients with asymptomatic brain metastases would benefit from this screening most because they would otherwise not be screened with brain MRI unless they develop neurologic symptoms. Early detection of brain metastasis by FDG PET/CT would change the tumor staging and patient management and may prolong survival by treating the brain metastases early with radiation.
For the first time, we have described increased posterior ocular bulb uptake in FDG PET/CT in detail and investigated the relationship between posterior ocular bulb uptake and the presence of cerebral metastasis. We acknowledge the limitations of our retrospective study and of the limited spatial resolution of PET/CT, which is at approximately 5 mm with the Gemini unit. Increased FDG activity at the posterior ocular bulb is a descriptive finding without detailed anatomic localization of involved tissue such as sclera, retina, choroids, or vessels. Prospective studies including neurologic and ophthalmologic examinations such as ophthalmoscopy, ocular pressure measurements, and electroretinography may help us understand the patho physiology of increased posterior ocular bulb uptake.
In conclusion, visually increased FDG uptake along the posterior ocular bulb is abnormal, may indicate intracranial structural changes, and may aid in the diagnosis of brain metastasis. However, the mechanism is unknown and needs to be further investigated in a prospective study that includes neurologic and ophthalmologic examinations.
Acknowledgments
We thank Penny Yost and Isaac Tran for technical assistance.
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