Cerebral Peduncle Angle: An Objective Criterion for Assessing Progressive Supranuclear Palsy Richardson Syndrome

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1 Neuroradiology/Head and Neck Imaging Original Research Fatterpekar et al. Cerebral Peduncle Angle Neuroradiology/Head and Neck Imaging Original Research Girish M. Fatterpekar 1 August Dietrich 1 Patrizia Pantano 2 Luca Saba 3 Edmond A. Knopp 1 Maria Cristina Piattella 2 Eytan Raz 1,2 Fatterpekar GM, Dietrich A, Pantano P, et al. Keywords: atrophy, cerebral peduncle, neurodegenerative disease, progressive supranuclear palsy, Richardson syndrome DOI:1.2214/AJR Received February 17, 214; accepted after revision November 12, Department of Radiology, New York University School of Medicine, 66 First Ave, 7th Fl, New York, NY 116. Address correspondence to E. Raz (eytan.raz@gmail.com). 2 Department of Neurology and Psychiatry, Neuroradiology Unit, IRCCS Neuromed, Pozilli (IS), Sapienza University of Rome, Rome, Italy. 3 Department of Radiology, Azienda Ospedaliero Universitaria, di Cagliari, Polo di Monserrato, Cagliari, Italy. AJR 215; 25: X/15/ American Roentgen Ray Society Cerebral Peduncle Angle: An Objective Criterion for Assessing Progressive Supranuclear Palsy Richardson Syndrome OBJECTIVE. Several criteria for time-consuming volumetric measurements of progressive supranuclear palsy Richardson syndrome subtype (PSP-RS) have been proposed. These often require image reconstruction in different planes for proper assessment. The purpose of this study was to evaluate the cerebral peduncle angle as a simple and reproducible measure of midbrain atrophy in patients with PSP-RS. MATERIALS AND METHODS. The records of 15 patients with PSP-RS were retrospectively identified. The records of 31 age-matched healthy control subjects, 15 patients with multiple-system atrophy, and 22 patients with Parkinson disease were included for comparison. Two neuroradiologists individually assessed these studies for midbrain atrophy by evaluating the cerebral peduncle angle, that is, the angle between the two cerebral peduncles. RESULTS. The cerebral peduncle angle measurements were 62.1 (SD, 6.8 ) in PSP-RS patients, 51.2 (SD, 1.1 ) in healthy control subjects, 55.7 (SD, 11.6 ) in patients with multiple-system atrophy, and 53.7 (SD, 8.5 ) in patients with Parkinson disease. A statistically significant difference was found in the cerebral peduncle angle measurements (observer 1, p =.15; observer 2, p =.4) between the PSP-RS patients and the other subgroups. Bland- Altman analysis showed a bias of.6 (95% limits of agreement, 6.9, 5.8 ), and intraobserver variability analysis showed a bias of.5 (4.1, 3 ). CONCLUSION. The cerebral peduncle angle is a simple, easy-to-calculate, and reproducible measure of midbrain atrophy. It is a useful criterion for differentiating patients with PSP- RS from healthy persons and from patients with multiple-system atrophy or Parkinson disease. P rogressive supranuclear palsy Richardson syndrome subtype (PSP-RS) is a neurodegenerative disease that is a type of Parkinson-plus syndrome [1]. Two clinical phenotypes of PSP are recognized: PSP-RS and PSP-parkinsonism (PSP-P). PSP-RS is characterized by early onset of postural instability and falls, supranuclear vertical gaze palsy, and cognitive dysfunction. PSP-P is characterized by asymmetric onset, tremor, and a moderate initial therapeutic response to levodopa and is frequently clinically confused with Parkinson disease (PD) [1 3]. Many patients with PSP-RS are initially thought to have multiple-system atrophy (MSA) or PD. Differentiation between these entities is challenging but important because each form has specific features that necessitate different approaches. For example, MSA has peculiar problems, including a blood pressure response to mineralocorticoids, midodrine, or other nondrug treatments, such as elevating the head of the bed or using salt tablets. As another example, levodopa, useful in PD, is not useful in MSA or PSP, other than for diagnostic trials. A notable pathologic difference is that the midbrain, particularly the superior cerebellar peduncles, undergoes atrophy in PSP [4, 5]. This atrophy is not seen in patients with MSA or PD [6, 7]. Numerous MRI-based quantitative measurements have been described for differentiating PSP-RS from PD and MSA [8 18]. Most of these proposed measurements are timeconsuming and sometimes require reconstructions in multiple planes and calculation of different ratios. We have observed that midbrain atrophy in PSP-RS patients results in widening of the interpeduncular cistern on axial MR images. Our hypothesis therefore was that the an- 386 AJR:25, August 215

2 Cerebral Peduncle Angle gle between the cerebral peduncles could be used to differentiate PSP-RS patients from healthy control subjects and patients with other neurodegenerative diseases. The purpose of our study was to evaluate the cerebral peduncle angle as a measure of midbrain atrophy and whether this angle can be used to identify patients with PSP-RS. Materials and Methods Case Selection A retrospective study was conducted to evaluate for midbrain atrophy in patient and control populations. Approval for this retrospective study was obtained from our institutional review board. The study was conducted in a HIPAA-compliant manner; the requirement for informed consent was waived. We reviewed our institutional medical records to identify the records of patients whose condition was diagnosed as PSP-RS on the basis of National Institute of Neurologic Disorders and Stroke PSP criteria [19]. The clinical features of the selected patients had to be compatible with the RS phenotype [3]. The records of 15 such patients were identified and included. Thirty-one age-matched healthy control subjects with imaging studies obtained for headache or dizziness with no history of alcoholism, chronic drug use, dementia, or gaze palsy and with normal ventricular size were included as the control population. The images of all of the healthy control subjects were assessed, and the radiologic reports were scrutinized to exclude patients with brain abnormalities. The records of 15 patients whose condition was diagnosed as MSA with predominant cerebellar ataxia, according to Gilman et al. [2], and of 22 patients with PD, according to Gelb et al. [21], were also retrospectively identified from our database and added to the study population for comparison. Studies with motion or susceptibility artifacts were excluded. MRI Protocol MRI examinations were performed with a 3-T whole-body system (Verio, Siemens Healthcare). The protocol included a 3D T1-weighted magnetization-prepared rapid gradient echo (MP-RAGE) sequence (TR/TE, 19/2.3; flip angle, 9 ; matrix, ; FOV, 24 mm 2 ; acquisition time, 3 minutes 48 seconds; number of axial slices, 176; slice thickness, 1 mm with no gap) through the whole brain. The MP-RAGE images so obtained were then postprocessed for calculation of the cerebral peduncle angle. Image Processing The DICOM images were anonymized and transferred to our PACS (ISite, Philips Healthcare). The analysis was performed by two fellowship-trained neuroradiologists blinded to the history and the category of the subjects. To standardize all the measurements, step 1 included reformatting the 3D axial T1-weighted images along the anterior commissure posterior commissure line (Fig. 1A). Step 2 was to precisely identify the axial plane, selected as a level below the mammillary bodies, for measuring the cerebral peduncle angle (Fig. 1B). This was done to ensure that the imaging plane used to measure the cerebral peduncle angle would remain constant throughout the study population. Step 3 included measurement of the cerebral peduncle angle. We defined the cerebral peduncle angle as the angle measured between the medial aspects of the cerebral peduncles with the posteriormost midline point of the interpeduncular cistern representing the vertex of the angle (Fig. 2). Step 4 was evaluation of the cerebral peduncle angle in the study population. The presence or absence of the hummingbird sign A so named because on midline sagittal T1-weighted MR images the midbrain resemble a hummingbird reflecting the presence of midbrain tegmentum atrophy, was also assessed [22, 23]. One of the two observers evaluated the entire pool of subjects twice the second evaluation 2 months after the first to establish intraobserver variability. Statistics The data were expressed as mean and SD or as median and range. ANOVA was performed to compare PSP-RS patients with MSA and PD patients and healthy subjects. For overall p.5, Bonferroni multiple comparison was used as a posttest. Using the Bonferroni correction, we set the significance level at p <.17 to adjust for multiple comparisons. Pearson correlation coefficient was used to test for any correlation between the cerebral peduncle angle and the age of the subject. Fig year-old healthy man. A, MR image shows plane used for reformatting axial 3D T1-weighted images along anterior commissure posterior commissure line (black line). B, Axial MR image just below mammillary bodies shows plane corresponding to dashed white line in A selected for calculation of cerebral peduncle angle. Fig year-old healthy man MR image shows cerebral peduncle angle as angle measured between medial aspects of cerebral peduncles with posteriormost midline point representing vertex of angle. This measurement is obtained in axial plane parallel to anterior commissure posterior commissure line and located below level of mammillary bodies (Fig. 1B). B AJR:25, August

3 Fatterpekar et al. Bland-Altman analysis was performed to evaluate for interobserver and intraobserver variability. ROC analysis was performed to determine the threshold cerebral peduncle angle that would best differentiate PSP-RS patients from healthy control subjects and patients with MSA or PD. A value of p <.5 was considered statistically significant. Statistics were calculated with SPSS software (version 21., IBM-SPSS). Graphs were built with Microsoft Excel for Mac, version 14. Results One patient with MSA, two patients with PD, and one healthy control subject were excluded because of the presence of motion or susceptibility artifacts. This resulted in a final study population of 15 PSP-RS patients (mean age, 69.1 [SD, 5.5] years; seven men, eight women), 14 MSA patients (mean age, 62.3 [SD, 1.5] years; seven men, seven women), 2 PD patients (mean age, 76.7 [SD, 9.3] years; 12 men, eight women), and 3 healthy control subjects (mean age, 67.7 [SD, 5.6] years; 16 men, 14 women). There were no significant differences in age and sex of the patients and control subjects. The hummingbird sign was detected in 1 of 15 patients with PSP-RS (66.7%) and five of 2 patients (25%) with PD. It was not detected in any control subjects or patients with MSA. The mean time spent for the reconstructions was 46.7 (SD, 5.9) seconds. The measurements of the cerebral peduncle angle for both readers are shown in Table 1 and Figure 3. Pertinent cases are shown in Figure 4. The results of ANOVA comparing PSP-RS patients with the other individual subgroups (MSA, PD, and healthy control subjects) were statistically significant. Using Bonferroni multiple comparison as a posttest, we found a statistically significant difference (p <.17) between the cerebral peduncle angle of patients with PSP-RS and those of all the other subjects. We also tested a possible correlation between cerebral peduncle angle and age: the Pearson correlation coefficient for PSP-RS patients was.38 (p =.163), for MSA patients was.45 (p =.879), for PD patients was.466 (p =.39), and for healthy control subjects was.221 (p =.267). Hence, a positive correlation was found only in the PD population. The interreader and intrareader agreements are shown in the Bland-Altman plots in Figures 5 and 6. Interobserver variability had a bias of.6 (95% limits of agreement, 6.9, 5.8 ), and intraobserver variability had bias of.5 (4.1, 3 ). TABLE 1: Measurements of Cerebral Peduncle Angle ( ) Reader Progressive Supranuclear Palsy Richardson Syndrome Multiple-System Atrophy ROC analysis was performed for the cerebral peduncle angle. The AUC was.795 (95% CI, ) for use of the cerebral peduncle angle in differentiating PSP-RS from other diseases (Fig. 7). With a cutoff cerebral peduncle angle value of 56 as a threshold, sensitivity of 86.7% and specificity of 64% were found. Discussion In this study, we found that the cerebral peduncle angle is a useful measure of midbrain atrophy and is helpful for differentiating PSP-RS patients from healthy control subjects and from patients with PD or MSA. Macroscopic neuropathologic studies of PSP-RS have shown atrophy of the superior cerebellar peduncle, the midbrain tegmentum more than the tectum, and the periaqueductal gray matter with relative preservation of the cerebral peduncles [4, 5, 24]. Such changes of midbrain atrophy cause some of the signs Parkinson Disease Healthy Control Subjects (6.7) 55.2 (11.2) 54.1 (8.4) 52.2 (9.7) (7.) 56.2 (12.1) 53.3 (8.7) 5.3 (11.).4 Average 62.1 (6.8) 55.7 (11.6) 53.7 (8.5) 51.2 (1.1).7 Note Values in parentheses are SD. a ANOVA; for reader 1, the first measurement was considered. Cerebral Peduncle Angle ( ) PSP MSA PD HC Fig. 3 Box-and-whisker chart shows cerebral peduncle angle measurements. Lower and upper limits of whiskers are minimum and maximum values. PSP = patients with progressive supranuclear palsy, MSA = patients with multiple-system atrophy, PD = patients with Parkinson disease, HC = healthy control subjects. described in the imaging literature, including the hummingbird sign, which refers to the appearance of the midbrain on midline sagittal T1-weighted MR images, and the Mickey Mouse sign, which reflects the appearance of the cerebral peduncles on axial T1-weighted MR images [22, 23]. These changes of midbrain atrophy subsequently result in prominence of the adjacent cisterns [25, 26]. Yuki et al. [25] found dilatation of the third ventricle, atrophy of the midbrain tegmentum, and enlargement of the interpeduncular cistern to be characteristic cross-sectional imaging findings in patients with PSP. Righini et al. [26] found progressive enlargement of the interpeduncular cistern in patients with PSP. Our description of a prominent cerebral peduncle angle in patients with PSP is a more objective criterion in assessments for midbrain atrophy and is consistent with the underlying pathologic features and findings in previous cross-sectional imaging studies. p a 388 AJR:25, August 215

4 Cerebral Peduncle Angle A C Fig. 4 Cerebral peduncle angle in one subject from each subgroup. A, 7-year-old man with progressive supranuclear palsy Richardson syndrome. Cerebral peduncle angle is 69. B, 62-year-old woman with multiple-system atrophy. Cerebral peduncle angle is 51. C, 75-year-old man with Parkinson disease. Cerebral peduncle angle is 52. D, 66-year-old man healthy control subject. Cerebral peduncle angle is 42. Difference ( ) CPA ( ) Readers 1 and SD 6.9 Mean SD 5.8 B D Multiple measurement criteria for assessing for midbrain atrophy and identifying patients with PSP have been proposed, including evaluation of the midbrain area by Oba et al. [1]; the anteroposterior midbrain diameter, area, and volume by Cosottini et al. [8]; the anteroposterior diameter of the midbrain, pons, and collicular plate by Warmuth-Metz et al. [12]; and measurement of the superior cerebellar peduncle with evaluation of multiple ratios such as that between the middle and superior cerebellar peduncles by Quattrone et al. [11]. Several other authors [9, 13, 14] used volumetric studies to assess for midbrain atrophy and PSP. These measurements have been found to be reliable with good sensitivity, such as the 91% specificity and 1% sensitivity for the midbrain area as measured with the Oba method [1]. Midbrain diameter was found to be useful for differentiating healthy control subjects from those with PSP, but MSA patients had similar findings, limiting the usefulness of this method in a general population [12]. Measurement of the superior cerebellar peduncle and ratio between the middle and superior cerebellar peduncles allowed discrimination of patients with PSP from those with MSA parkinsonian type and those with PD and control participants with sensitivity of 1%, specificity of 1%, and positive predictive value of 1%. Although these measurement criteria have potential in assessment for PSP, they are time-consuming and sometimes require multiplanar reconstructions and supplementary use of additional software. Our study shows that the cerebral peduncle angle is a simple to calculate, quick to perform, and reproducible measure of midbrain atrophy in PSP-RS patients. At pathologic examination, PSP-RS is characterized by midbrain atrophy. The underlying pathologic mechanism is different in PD, in which the brainstem is grossly normal but mild frontal atrophy and substantia nigra degeneration are present [6, 7]. Neuropathologically, there is no substantial midbrain atrophy in MSA. The MSA parkinsonian type subgroup has atrophy of the posterolateral putamen, whereas patients with clinically significant cerebellar signs have atrophy of the pons, Fig. 5 Interobserver agreement. Graph shows Bland-Altman limits of agreement for measurement of cerebral peduncle angle (CPA) between readers 1 and 2. CPAs obtained from two observers measurements are plotted against difference between observers measurements. Dashed lines represent 95% limits of agreement. Interobserver variability shows bias of.6 (6.9, 5.8 ). AJR:25, August

5 Fatterpekar et al. Difference ( ) inferior olive, and cerebellar cortex. Previous imaging studies with different linear measurement criteria have been conducted to evaluate for midbrain atrophy in patients with PSP [1 12, 23, 27]. Some studies [1, 11, 28, 29], however, did not differentiate PSP patients from PD or MSA patients. In our study, we found a statistically significant difference in cerebral peduncle angle measurements when we compared the MSA and PD populations. Our finding is consistent with the underlying pathologic changes. Furthermore, other studies have shown that with CPA ( ) Two Measurements by Reader SD 4.1 Mean SD Fig. 6 Intraobserver agreement. Graph shows Bland-Altman limits of agreement for measurement of cerebral peduncle angle (CPA) at two time points for reader 1 plotted against mean difference between two measurements. Dashed lines represent 95% limits of agreement. Intraobserver variability shows bias of.5 (4.1, 3 ). Sensitivity (%) Specificity (%) Fig. 7 Graph shows ROC curve of cerebral peduncle angle in differentiation of progressive supranuclear palsy patents from healthy control subjects and from patients with multiple system atrophy or Parkinson disease. The AUC was.795 (95% CI, ) with standard error of.581; z statistic, 5.7; p <.1 (AUC,.5). With 56 as threshold for cerebral peduncle angle, sensitivity was 86.7%, and specificity was 64%. advancing age, there is progressive midbrain atrophy [3]. Our study showed that the degree of midbrain atrophy is much more pronounced in PSP patients than in healthy agematched control subjects. There were limitations to our study. The primary limitation was the fairly small number of PSP-RS patients (n = 15). However, this number is similar to that reported in most other studies of imaging of PSP-RS and is therefore reasonable given the uncommon occurrence of the disease. The other limitation was that all of the patients included in the PSP population had established PSP-RS; there were no cases of the parkinsonian type of PSP, a rarer variant. The usefulness of the cerebral peduncle angle in the diagnosis of early cases of PSP-RS remains to be determined, and the overlapping of the cerebral peduncle angle obtained for the different subgroups confirms this limitation. Longitudinal studies with patient populations that include those with suspected and those with diagnosed PSP-RS may shed some light on this topic. Conclusion The cerebral peduncle angle is a single simple, easy-to-calculate, reproducible measure of midbrain atrophy. It can be a useful criterion for differentiating PSP-RS patients from healthy subjects and patients with MSA or PD. References 1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy: a heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 1: Burn DJ, Lees AJ. Progressive supranuclear palsy: where are we now? Lancet Neurol 22; 1: Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson s syndrome and PSP-parkinsonism. Brain 25; 128: Tsuboi Y, Slowinski J, Josephs KA, et al. Atrophy of superior cerebellar peduncle in progressive supranuclear palsy. Neurology 23; 6: Aiba I, Hashizume Y, Yoshida M, et al. Relationship between brainstem MRI and pathological findings in progressive supranuclear palsy: study in autopsy cases. J Neurol Sci 1997; 152: Wenning GK, Colosimo C, Geser F, et al. Multiple system atrophy. Lancet Neurol 24; 3: Nicoletti G, Fera F, Condino F, et al. MR imaging of middle cerebellar peduncle width: differentiation of multiple system atrophy from Parkinson disease. Radiology 26; 239: Cosottini M, Ceravolo R, Faggioni L, et al. Assessment of midbrain atrophy in patients with progressive supranuclear palsy with routine magnetic resonance imaging. Acta Neurol Scand 27; 116: Gröschel K, Hauser TK, Luft A, et al. Magnetic resonance imaging-based volumetry differentiates progressive supranuclear palsy from corticobasal degeneration. Neuroimage 24; 21: Oba H, Yagishita A, Terada H, et al. New and reliable MRI diagnosis for progressive supranuclear 39 AJR:25, August 215

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