RESEARCH
ARTICLE
Five-Year Follow-up of Substantia Nigra Echogenicity in Idiopathic REM Sleep Behavior Disorder nica Serradell, Bsc,1 Klaus Seppi, MD,2 Francesc Valldeoriola, MD,1 Alex Iranzo, MD,1†* Heike Stockner, MD,2† Mo Luis Molinuevo, MD,1 Isabel Vilaseca, MD,3 Thomas Mitterling, MD,2 Carles Gaig, MD,1 Birgit Frauscher, MD,2 Jose €gl, MD,2 Eduard Tolosa, MD,1 and Werner Poewe, MD2 Dolores Vilas, MD,1 Joan Santamaria, MD,1 Birgit Ho 1
Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain 2 Innsbruck Medical University, Department of Neurology, Innsbruck, Austria 3 Otorhinolaryngology Service, Hospital Clinic Barcelona, Spain
ABSTRACT:
Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson’s disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow-up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty-one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy
Hyperechogenicity of the substantia nigra (SN1) detected by transcranial sonography (TCS) has been proposed as a marker for Parkinson disease (PD).1,2 It is present in most of PD patients,3-5 and in the healthy
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*Correspondence to: Alex Iranzo, Neurology Service, Hospital Clinic de Barcelona, C/ Villarroel 170, Barcelona 08036, Spain, E-mail: [email protected] Funding agencies: No financial support was received for this work.
Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. †
Both authors contributed equally to this work.
Received: 30 June 2014; Revised: 25 September 2014; Accepted: 26 September 2014 Published online 10 November 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26055
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was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 6 0.09 cm2 vs. 0.19 6 0.07 cm2; P 5 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P 5 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow-up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains C 2014 International Parkinson and stable over time. V Movement Disorder Society
K e y W o r d s : substantia nigra echogenicity; transcranial sonography; follow-up; REM sleep behavior disorder; Parkinson’s disease
population it is associated with an increased risk of developing PD.6 SN1 is a trait rather than a progression marker of PD, because longitudinal studies have shown that the size of the increased echo signal does not change with time in both manifested PD7,8 and healthy subjects.9 It is thought that SN1 may be detectable in individuals at the prodromal stage of PD before the occurrence of parkinsonism. At which point of the prodromal period SN1 emerges, and whether the echogenic size of the substantia nigra increases with time, are unknown. Most patients with idiopathic rapid eye movement (REM) behavior disorder (IRBD) are eventually diagnosed with the synucleinopathies PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).10-14 Approximately 35% to 50% of IRBD
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patients show features indicative of subclinical substantia nigra dysfunction such as SN1 or decreased striatal dopamine transporter binding on functional neuroimaging.15-17 The combination of SN1 and decreased striatal dopamine transport uptake has been shown useful to identify IRBD individuals at increased short-term risk for developing a synucleinopathy.16 In IRBD, however, whether SN1 alone is sufficient to predict the conversion to a synucleinopathy, and whether the echogenic size of the substantia nigra changes with time, are unknown. In the current prospective study, we aimed to assess (1) the utility of TCS alone to identify IRBD patients who are later diagnosed with a synucleinopathy in a relative long-term observational period of 5 years, and (2) whether the echogenic size of the substantia nigra increases with time in IRBD.
Methods In a study done in October 2007, a cohort of 55 IRBD individuals, diagnosed by clinical history and video-polysomnography,10-12 underwent baseline TCS, and results were reported.15 Patients were clinically followed-up, and when neurological symptoms appeared they were diagnosed with either PD,18 DLB,19 or MSA.20 After 5 years of baseline TCS, patients’ charts were reviewed, and available individuals were invited for clinical assessment and repeated TCS examination in October 2012.
Transcranial Sonography Assessment Baseline and repeated TCS examinations were performed by the same experienced ultrasound examiner (H.S.), using the same ultrasound device (Logiq 7; General Electric, Milwaukee, WI, USA) and the same systems adjustments.15 The TCS examinations were performed with a 2.5-MHz transducer from both sides, using the acoustic temporal bone window. The penetration depth was 16 cm, and the dynamic range was 45 to 50 dB. Areas of echogenicity of the substantia nigra were manually encircled on digitally stored images, and the total area of echogenic signals in the substantia nigra region was measured. Echogenic areas of each side were analyzed separately. The side of greater value of substantia nigra echogenicity was used for statistical analysis. Hyperechogenicity (SN1) was defined as an area of at least 0.20 cm2 on one side, as established at the baseline examination.15 Areas of echogenicity of less than 0.20 cm2 were classified as normoechogenic (SN-). The sonographer performed TCS investigations in the same laboratory rooms at the Hospital Clinic de Barcelona in the Spanish patients (44 at baseline and 39 at the 5-year follow-up) and at the Innsbruck Medical University in the Austrian patients (11 at baseline
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and nine at the 5-year follow-up). The ultrasound examiner was not involved in diagnosis of IRBD, routine clinical follow-up visits at sleep centers, diagnosis of emerging neurological diseases, and the neurological examination at the time of both TCS investigations. The sonographer was also blinded to baseline TCS results. To ensure blind TCS examination, a group of 17 healthy controls underwent TCS at the 5year follow-up assessment. The sonographer was not aware of the existence of a group of controls and was masked to the status of the participants (disease-free IRBD, PD, DLB, or MSA) who presented in a random order, lying in the supine position before the start of the TCS examination in a dark room. Controls’ data were not used in the current study. The study was approved by the ethics committee at our institutions, and all patients or their caregivers, when appropriate, gave written informed consent.
Statistical Analysis Descriptive demographical, clinical, and TCS data are given in means, standard deviations, and percentages. Correlation coefficients of the ultrasound marker over time were assessed with Spearman rank correlation coefficients. Intraclass correlation coefficients derived using a one-way random effects analysis of variance model were determined for the left, right, and mean substantia nigra size and the greater substantia nigra echogenicity side. Sensitivity, specificity, positive predictive value, negative predictive value, and relative risk, along with 95% confidence intervals (CIs), were estimated for baseline SN1, as a marker to predict the development of an emerging synucleinopathy, or PD and DLB separately. Differences in the area of the echogenic size of the substantia nigra and in the percentage of patients with SN1 were compared between the first and second TCS examinations using the McNemar test and Wilcoxon signed ranks test, when appropriate. P values less than 0.05 were considered significant. All analyses were done with SPSS version 20.0.
Results Baseline TCS Examination Fifty-five IRBD patients, 47 men and eight women, were assessed at baseline in 2007. Their mean age was 68.9 6 7.8 years, mean age at RBD onset was 59.9 6 8.1 years, and mean RBD duration was 8.9 6 5.3 years. Nineteen (34.5%) patients had SN1, 32 (58.2%) showed SN-, and 4 (7.3%) had insufficient temporal acoustic bone window. The mean echogenic size of the substantia nigra was 0.20 6 0.09 cm2, which was significantly larger when compared with a
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TABLE 1. Clinical status according to baseline TCS Clinical Status at Second Examination TCS Results at Initial Examination
SN1 (n 5 19) SN2 (n 5 32) Lack of bone window (n 5 4)
IRBD (n 5 33)
PD (n 5 11)
DLB (n 5 9)
MSA (n 5 1)
Lost (n 5 1)
10 (52.7%) 21 (65.6%) 2 (50%)
4 (21%) 5 (15.6%) 2 (50%)
4 (21%) 5 (15.6%) 0
0 1 (3.2%) 0
1 (5.3%) 0 0
TCS, transcranial sonography; SN1, hyperechogenicity of substantia nigra; SN-, normoechogenicity of substantia nigra; IRBD, idiopathic REM sleep behavior disorder; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy.
group of 574 healthy individuals from the general population.15
the values but also high intrarater reliability using the same equipment.
Baseline SN1 as a Predictor of a Synucleinopathy
Comparison of Substantia Nigra Echogenicity Between the First and Second TCS Examination
By the 2012 assessment, 33 (60%) patients remained disease-free, 21 (38.2%) were diagnosed with a synucleinopathy, and one (1.8%) was lost to follow-up with the diagnosis of IRBD at his last visit. Emerging disorders were PD in 11 subjects, DLB in nine, and MSA in one. The mean interval period between diagnosis of a neurological disease and second TCS assessment was 1.5 6 1.5 years. Of the 19 patients who had SN1 at baseline, 10 (52.7%) remained disease-free, eight (42.0%) developed a synucleinopathy (four PD and four DLB), and one (5.3%) was lost (Table 1). Of the 32 patients who had SN- at baseline, 21 (65.6%) remained disease-free and 11 (34.4%) developed a synucleinopathy (five PD, five DLB, and one MSA). Of the four patients who had lack of temporal bone window, two (50%) remained disease-free and the other two (50%) developed PD. The sensitivity of baseline SN1 to predict the development of a synucleinopathy after 5 years of follow-up was 42.1% (95% confidence interval [CI] 5 19.9%64.3%), specificity was 67.7% (95% CI 5 51.3%84.2%), positive predictive value was 44.4% (95% CI 5 21.5%-67.4%), negative predictive value was 65.6% (95% CI 5 49.1%-82.1%), and relative risk was 1.29 (95% CI 5 0.63-2.61). Similar results were obtained when the PD and DLB groups were evaluated separately (data not shown).
Reproducibility and Reliability of TCS Examinations Correlation coefficients of the ultrasound marker over time were excellent for the left, right, and mean substantia nigra size and also the greater substantia nigra echogenicity side (Spearman rank r 5 0.81 and above, each P < 0.001). This also occurred for the intraclass correlation coefficients (0.88 and above, each P < 0.001), demonstrating not only low variability of
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At the 5-year assessment, 48 (87.3%) subjects (40 men and eight women with a mean age of 73.56 6 7.59 years) underwent repeated TCS. They had diagnoses of IRBD in 30, PD in nine, DLB in eight, and MSA in one. The remaining seven (12.7%) patients did not undergo repeated TCS because five had already died (two with the clinical antemortem diagnoses of PD, one with DLB, and two with IRBD), one with IRBD was unable to participate, and one with the diagnosis of IRBD was lost to follow-up. At baseline TCS assessment, these seven patients had SN1 in four cases and SN- in three. Among the 48 patients who underwent repeated TCS assessment, 15 (31.3%) had SN1, 29 (60.5%) had SN-, and 4 (8.2%) had insufficient bone window at the baseline examination (Fig. 1). At the second examination, these 48 subjects displayed SN1 in 18 (37.5%) cases, SN- in 24 (50.0%), and insufficient bone window in six (12.5%). In these 48 individuals, no differences were detected between the first and second TCS examinations in the mean size of the substantia nigra (0.20 6 0.09 cm2 vs. 0.19 6 0.07 cm2; mean difference of 20.0005 6 0.48 cm2; P 5 0.777) and in the percentage of patients with SN1 (33.3% vs. 42.8%, P 5 0.125). The mean size of the substantia nigra was not different between the first and second TCS examinations among patients who converted to PD (0.20 6 0.08 cm2 vs. 0.21 6 0.09 cm2; mean difference of 20.0086 6 0.05 cm2; P 5 0.673) or who converted to DLB (0.21 6 0.09 cm2 vs. 0.20 6 0.06 cm2; mean difference of 0.0013 6 0.04 cm2; P 5 0.492).
Evolution of SN Echogenicity Over Time Of the 19 patients who had SN1 at baseline, repeated TCS showed SN1 in 14 (73.7%), insufficient bone window in in one (5.3%), and TCS was not done in four (21.1%) cases. None of the subjects who showed SN1 at baseline displayed SN- at the second evaluation (Table 2, Fig. 2). Of the four patients who
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FIG. 1. Baseline transcranial sonography findings of patients who underwent the follow-up examination.
changed from SN- to SN1 at the second assessment, two remained disease free, one developed PD, and one developed DLB.
Relationship Between TCS Results and Clinical Status Of the 11 patients with baseline SN- who developed a synucleinopathy, repeated TCS examination could be done in 10 individuals, showing SN- in eight (80%) and a change to SN1 in two (20%). Among the 33 subjects that were disease-free at the second assessment, 21 (63.6%) had SN-, 10 (30.3%) had SN1, and two (6.1%) had insufficient bone window at baseline. At the second evaluation, 16 (48.5%) still had SN-, 10 (30.3%) had SN1, four (12.1%) had insufficient bone window, and three (9.1%) could not undergo TCS. Of the 21 patients that were diagnosed with a synucleinopathy, 11 (52.4%) had SN-, eight (38.1%) had
SN1, and two (9.5%) had insufficient bone window at the first assessment. At the second evaluation, eight (38.1%) had SN1, eight (38.1%) had SN-, two (9.5%) had insufficient bone window, and three (14.3%) did not undergo TCS because they were deceased.
TCS Results According to Type of Synucleinopathy Eleven patients, eight men and three women, were diagnosed with PD at the mean age of 76.1 6 5.8 years. Eight exhibited the akinetic-rigid motor subtype and three the mixed motor subtype. SN1 was detected in four (36.4%) patients in the first evaluation and in four (36.4%) in the second assessment, all but two with the akinetic-rigid motor subtype. SN1 was unilateral in two patients and bilateral in three. Five (45.5%) patients had SN- in the baseline evaluation and three (27.3%) in the later examination.
TABLE 2. Transcranial sonography findings at the initial and second examinations TCS Results at Second Examination TCS Results at Initial Examination
SN1 (n 5 19) SN2 (n 5 32) Lack of bone window (n 5 4)
SN1 (n 5 18)
SN- (n 5 24)
Lack of Bone Window (n 5 6)
Not Performed (n 5 7)a
14 (73.7%) 4 (12.5%) 0
0 24 (75%) 0
1 (5.3%) 1 (3.1%) 4 (100%)
4 (21.1%) 3 (9.4%) 0
TCS, transcranial sonography; SN1, hyperechogenicity of substantia nigra; SN-, normoechogenicity of substantia nigra. a Reasons for not performing TCS at second assessment were death (n 5 5), unable to participate (n 5 1) and lost during follow-up (n 5 1).
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FIG. 2. Baseline and follow-up transcranial sonography findings according to clinical status at follow-up examination.
Insufficient bone window was seen in the same two patients at both TCS evaluations. Two PD patients died before the second TCS examination. Nine men were diagnosed with DLB at the mean age of 73.9 6 5.5 years. SN1 was detected in four (44.4%) patients in both examinations. SN1 was unilateral in two patients and bilateral in two. SN- was seen in five subjects in the first evaluation (55.6%) and in four (44.4%) in the follow-up evaluation. One patient who showed SN1 died before the second TCS examination. A 75-year-old woman was diagnosed with MSA and exhibited SN- at both assessments. The IRBD subject who was unable to undergo repeated TCS had SN- at baseline. The patient who was lost had SN1 at baseline. Among the two cases that died with the diagnosis of IRBD during the follow-up, one had SN1 and the other had SN- at baseline.
Discussion To the best of our knowledge, this is the first prospective longitudinal study evaluating TCS in IRBD. We have found that SN1 by itself is not a marker for the development of PD and other synucleinopathies after 5 years of close clinical follow-up. Because we previously found that the combination of decreased striatal dopamine transporter uptake and SN1 identified the early conversion to a synucleinopathy,16
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investigating whether dopamine transporter imaging is able to identify this same risk independently might be advisable. The area of the echogenicity of the substantia nigra did not change with time in IRBD, even in those patients who converted to PD. Most of the patients who had SN- at baseline and later developed a synucleinopathy had this same echo feature at the second assessment. No significant differences were seen between the first and second TCS examinations in the mean size of the substantia nigra and in the percentage of patients with SN1. These findings were disclosed for the whole IRBD cohort and also for the subgroup of patients who developed PD. Thus, the size of the substantia nigra, as assessed by serial TCS, does not reflect disease progression during the course of the prodromal phase of PD in subjects with IRBD. Most subjects with IRBD are eventually diagnosed with PD, DLB, and MSA.12-14 Thus, IRBD seems to be a suitable population for testing disease-modifying therapies in future clinical trials. For the design of such trials, finding a marker capable of identifying subjects with a high risk for the early development of parkinsonism and dementia, and also monitoring disease progression, showing longitudinal changes over time, are important. Available data in IRBD indicate that the combinations of SN1 plus decreased striatal dopamine transporter uptake16 and hyposmia plus color vision loss21 are strategies that identify subjects
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with an increased risk of developing a synucleinopathy after 2.5 and 5 years of follow-up. In IRBD, serial dopamine transporter imaging shows progressive decline in striatal tracer binding.22 In contrast, olfaction and color vision functions do not worsen with time in IRBD.21,23 In the current study, we have shown that for future disease-modifying trials in IRBD, TCS by itself is not useful because it does not identify patients at high risk for the development of a synucleinopathy and because it does not show changes in echo size with time. SN1 is found in 8% to 16% of healthy adults and constitutes an established risk maker for PD.24-29 A prospective population-based study involving 1,261 healthy people older than 50 years showed that SN1 is associated with a 20-fold increased risk to develop PD within the next 5 years, with a positive predictive value of 6.5%.6 Our study in IRBD showed that the SN1 relative risk for incident PD was only 1.42, whereas the positive predictive value was 22.2%. This positive predictive value of SN1 for PD in IRBD is higher than in the general population older than 50 years (22.2% vs. 6.5%) within the same 5-year period of observation.6 This might be explained by the fact that IRBD is per se a much stronger risk factor for PD than age in the general population. The occurrence of PD in our IRBD cohort after a 5-year observational period far exceeds the prevalence of PD in the general population of similar age (20% versus 2%).30 In PD, enlarged echogenic substania nigra occurs in approximately 90% of patients and is thought to reflect increased iron deposition and microglial activation within the substantia nigra.1 SN1 in PD is not a marker of progressive nigral degeneration, because it is neither associated with severity of parkinsonism4,5,31,32 nor with the degree of dopaminergic deficit detected by functional neuroimaging,24-26 and the size of the echogenic area is stable in the course of disease in spite of clinical disease progression.7,8 In our study, 11 patients were diagnosed with PD at the mean age of 76 years, and most showed the akinetic-rigid motor subtype. Among the seven PD patients who had sufficient acoustic temporal bone window at the second assessment, the size of the substantia nigra was stable, and three (43%) subjects had SN-. We do not know the reason for this relatively high percentage of SN- found in our PD sample. This result might be related to the small size of our cohort. Alternatively, a possible explanation is that these PD subjects (in whom RBD preceded parkinsonism) constitute a subtype of the disease in which normoechogenicity is more common. As we noted in our sample, PD patients in whom RBD antedates motor signs are characterized by older age at disease diagnosis (at approximately 72-74 years) and the akinetic-rigid motor subtype.12-14 A higher proportion of SN- may be one of the characteristics in this specific PD subgroup. Of note, studies in PD have shown that
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SN- is associated with older age at disease onset31 and that smaller substantia nigra echogenic size correlates with older age at PD onset.29 SN1 has also been reported in DLB in one study involving 14 subjects in which SN1 had a similar prevalence as in PD.34 In contrast, SN1 is not common in MSA.35,36 In our study, nine men were diagnosed with DLB, and SN1 occurred in approximately half of the cases, whereas SN1 was absent at both examinations in the only patient who developed MSA. Some limitations should be noted. First, the size of our cohort was somewhat small, and this can influence further evaluations in the follow-up. Second, at the end of the study, 60% of the individuals remained diseasefree. Longer follow-up with higher conversion rate will be required to confirm the results of our study. Finally, sonographic assessment of the substantia nigra was not possible in 8% to 12% of our sample because of insufficient temporal bone window. Strengths of this study are that most (87%) of the patients underwent a second TCS examination, the sonographer was blinded and used the same TCS machine and adjustments at both examinations, and high intrarater reproducibility, which indicates low variability and optimal reliability in our substantia nigra measurements. In summary, our study shows that TCS alone is not helpful in identifying those subjects who will convert to PD or a synucleiopathy within a 5-year period, and that serial TCS cannot be used to monitor the degenerative process within the substantia nigra during the prodromal stage of PD.
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Gaenslen A, Unmuth B, Godau J, et al. The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson’s disease: a prospective blinded study. Lancet Neurol 2008;7:417-424.
ARTICLE
Five-Year Follow-up of Substantia Nigra Echogenicity in Idiopathic REM Sleep Behavior Disorder nica Serradell, Bsc,1 Klaus Seppi, MD,2 Francesc Valldeoriola, MD,1 Alex Iranzo, MD,1†* Heike Stockner, MD,2† Mo Luis Molinuevo, MD,1 Isabel Vilaseca, MD,3 Thomas Mitterling, MD,2 Carles Gaig, MD,1 Birgit Frauscher, MD,2 Jose €gl, MD,2 Eduard Tolosa, MD,1 and Werner Poewe, MD2 Dolores Vilas, MD,1 Joan Santamaria, MD,1 Birgit Ho 1
Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain 2 Innsbruck Medical University, Department of Neurology, Innsbruck, Austria 3 Otorhinolaryngology Service, Hospital Clinic Barcelona, Spain
ABSTRACT:
Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson’s disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow-up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty-one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy
Hyperechogenicity of the substantia nigra (SN1) detected by transcranial sonography (TCS) has been proposed as a marker for Parkinson disease (PD).1,2 It is present in most of PD patients,3-5 and in the healthy
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*Correspondence to: Alex Iranzo, Neurology Service, Hospital Clinic de Barcelona, C/ Villarroel 170, Barcelona 08036, Spain, E-mail: [email protected] Funding agencies: No financial support was received for this work.
Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. †
Both authors contributed equally to this work.
Received: 30 June 2014; Revised: 25 September 2014; Accepted: 26 September 2014 Published online 10 November 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26055
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was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 6 0.09 cm2 vs. 0.19 6 0.07 cm2; P 5 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P 5 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow-up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains C 2014 International Parkinson and stable over time. V Movement Disorder Society
K e y W o r d s : substantia nigra echogenicity; transcranial sonography; follow-up; REM sleep behavior disorder; Parkinson’s disease
population it is associated with an increased risk of developing PD.6 SN1 is a trait rather than a progression marker of PD, because longitudinal studies have shown that the size of the increased echo signal does not change with time in both manifested PD7,8 and healthy subjects.9 It is thought that SN1 may be detectable in individuals at the prodromal stage of PD before the occurrence of parkinsonism. At which point of the prodromal period SN1 emerges, and whether the echogenic size of the substantia nigra increases with time, are unknown. Most patients with idiopathic rapid eye movement (REM) behavior disorder (IRBD) are eventually diagnosed with the synucleinopathies PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).10-14 Approximately 35% to 50% of IRBD
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patients show features indicative of subclinical substantia nigra dysfunction such as SN1 or decreased striatal dopamine transporter binding on functional neuroimaging.15-17 The combination of SN1 and decreased striatal dopamine transport uptake has been shown useful to identify IRBD individuals at increased short-term risk for developing a synucleinopathy.16 In IRBD, however, whether SN1 alone is sufficient to predict the conversion to a synucleinopathy, and whether the echogenic size of the substantia nigra changes with time, are unknown. In the current prospective study, we aimed to assess (1) the utility of TCS alone to identify IRBD patients who are later diagnosed with a synucleinopathy in a relative long-term observational period of 5 years, and (2) whether the echogenic size of the substantia nigra increases with time in IRBD.
Methods In a study done in October 2007, a cohort of 55 IRBD individuals, diagnosed by clinical history and video-polysomnography,10-12 underwent baseline TCS, and results were reported.15 Patients were clinically followed-up, and when neurological symptoms appeared they were diagnosed with either PD,18 DLB,19 or MSA.20 After 5 years of baseline TCS, patients’ charts were reviewed, and available individuals were invited for clinical assessment and repeated TCS examination in October 2012.
Transcranial Sonography Assessment Baseline and repeated TCS examinations were performed by the same experienced ultrasound examiner (H.S.), using the same ultrasound device (Logiq 7; General Electric, Milwaukee, WI, USA) and the same systems adjustments.15 The TCS examinations were performed with a 2.5-MHz transducer from both sides, using the acoustic temporal bone window. The penetration depth was 16 cm, and the dynamic range was 45 to 50 dB. Areas of echogenicity of the substantia nigra were manually encircled on digitally stored images, and the total area of echogenic signals in the substantia nigra region was measured. Echogenic areas of each side were analyzed separately. The side of greater value of substantia nigra echogenicity was used for statistical analysis. Hyperechogenicity (SN1) was defined as an area of at least 0.20 cm2 on one side, as established at the baseline examination.15 Areas of echogenicity of less than 0.20 cm2 were classified as normoechogenic (SN-). The sonographer performed TCS investigations in the same laboratory rooms at the Hospital Clinic de Barcelona in the Spanish patients (44 at baseline and 39 at the 5-year follow-up) and at the Innsbruck Medical University in the Austrian patients (11 at baseline
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and nine at the 5-year follow-up). The ultrasound examiner was not involved in diagnosis of IRBD, routine clinical follow-up visits at sleep centers, diagnosis of emerging neurological diseases, and the neurological examination at the time of both TCS investigations. The sonographer was also blinded to baseline TCS results. To ensure blind TCS examination, a group of 17 healthy controls underwent TCS at the 5year follow-up assessment. The sonographer was not aware of the existence of a group of controls and was masked to the status of the participants (disease-free IRBD, PD, DLB, or MSA) who presented in a random order, lying in the supine position before the start of the TCS examination in a dark room. Controls’ data were not used in the current study. The study was approved by the ethics committee at our institutions, and all patients or their caregivers, when appropriate, gave written informed consent.
Statistical Analysis Descriptive demographical, clinical, and TCS data are given in means, standard deviations, and percentages. Correlation coefficients of the ultrasound marker over time were assessed with Spearman rank correlation coefficients. Intraclass correlation coefficients derived using a one-way random effects analysis of variance model were determined for the left, right, and mean substantia nigra size and the greater substantia nigra echogenicity side. Sensitivity, specificity, positive predictive value, negative predictive value, and relative risk, along with 95% confidence intervals (CIs), were estimated for baseline SN1, as a marker to predict the development of an emerging synucleinopathy, or PD and DLB separately. Differences in the area of the echogenic size of the substantia nigra and in the percentage of patients with SN1 were compared between the first and second TCS examinations using the McNemar test and Wilcoxon signed ranks test, when appropriate. P values less than 0.05 were considered significant. All analyses were done with SPSS version 20.0.
Results Baseline TCS Examination Fifty-five IRBD patients, 47 men and eight women, were assessed at baseline in 2007. Their mean age was 68.9 6 7.8 years, mean age at RBD onset was 59.9 6 8.1 years, and mean RBD duration was 8.9 6 5.3 years. Nineteen (34.5%) patients had SN1, 32 (58.2%) showed SN-, and 4 (7.3%) had insufficient temporal acoustic bone window. The mean echogenic size of the substantia nigra was 0.20 6 0.09 cm2, which was significantly larger when compared with a
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TABLE 1. Clinical status according to baseline TCS Clinical Status at Second Examination TCS Results at Initial Examination
SN1 (n 5 19) SN2 (n 5 32) Lack of bone window (n 5 4)
IRBD (n 5 33)
PD (n 5 11)
DLB (n 5 9)
MSA (n 5 1)
Lost (n 5 1)
10 (52.7%) 21 (65.6%) 2 (50%)
4 (21%) 5 (15.6%) 2 (50%)
4 (21%) 5 (15.6%) 0
0 1 (3.2%) 0
1 (5.3%) 0 0
TCS, transcranial sonography; SN1, hyperechogenicity of substantia nigra; SN-, normoechogenicity of substantia nigra; IRBD, idiopathic REM sleep behavior disorder; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy.
group of 574 healthy individuals from the general population.15
the values but also high intrarater reliability using the same equipment.
Baseline SN1 as a Predictor of a Synucleinopathy
Comparison of Substantia Nigra Echogenicity Between the First and Second TCS Examination
By the 2012 assessment, 33 (60%) patients remained disease-free, 21 (38.2%) were diagnosed with a synucleinopathy, and one (1.8%) was lost to follow-up with the diagnosis of IRBD at his last visit. Emerging disorders were PD in 11 subjects, DLB in nine, and MSA in one. The mean interval period between diagnosis of a neurological disease and second TCS assessment was 1.5 6 1.5 years. Of the 19 patients who had SN1 at baseline, 10 (52.7%) remained disease-free, eight (42.0%) developed a synucleinopathy (four PD and four DLB), and one (5.3%) was lost (Table 1). Of the 32 patients who had SN- at baseline, 21 (65.6%) remained disease-free and 11 (34.4%) developed a synucleinopathy (five PD, five DLB, and one MSA). Of the four patients who had lack of temporal bone window, two (50%) remained disease-free and the other two (50%) developed PD. The sensitivity of baseline SN1 to predict the development of a synucleinopathy after 5 years of follow-up was 42.1% (95% confidence interval [CI] 5 19.9%64.3%), specificity was 67.7% (95% CI 5 51.3%84.2%), positive predictive value was 44.4% (95% CI 5 21.5%-67.4%), negative predictive value was 65.6% (95% CI 5 49.1%-82.1%), and relative risk was 1.29 (95% CI 5 0.63-2.61). Similar results were obtained when the PD and DLB groups were evaluated separately (data not shown).
Reproducibility and Reliability of TCS Examinations Correlation coefficients of the ultrasound marker over time were excellent for the left, right, and mean substantia nigra size and also the greater substantia nigra echogenicity side (Spearman rank r 5 0.81 and above, each P < 0.001). This also occurred for the intraclass correlation coefficients (0.88 and above, each P < 0.001), demonstrating not only low variability of
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At the 5-year assessment, 48 (87.3%) subjects (40 men and eight women with a mean age of 73.56 6 7.59 years) underwent repeated TCS. They had diagnoses of IRBD in 30, PD in nine, DLB in eight, and MSA in one. The remaining seven (12.7%) patients did not undergo repeated TCS because five had already died (two with the clinical antemortem diagnoses of PD, one with DLB, and two with IRBD), one with IRBD was unable to participate, and one with the diagnosis of IRBD was lost to follow-up. At baseline TCS assessment, these seven patients had SN1 in four cases and SN- in three. Among the 48 patients who underwent repeated TCS assessment, 15 (31.3%) had SN1, 29 (60.5%) had SN-, and 4 (8.2%) had insufficient bone window at the baseline examination (Fig. 1). At the second examination, these 48 subjects displayed SN1 in 18 (37.5%) cases, SN- in 24 (50.0%), and insufficient bone window in six (12.5%). In these 48 individuals, no differences were detected between the first and second TCS examinations in the mean size of the substantia nigra (0.20 6 0.09 cm2 vs. 0.19 6 0.07 cm2; mean difference of 20.0005 6 0.48 cm2; P 5 0.777) and in the percentage of patients with SN1 (33.3% vs. 42.8%, P 5 0.125). The mean size of the substantia nigra was not different between the first and second TCS examinations among patients who converted to PD (0.20 6 0.08 cm2 vs. 0.21 6 0.09 cm2; mean difference of 20.0086 6 0.05 cm2; P 5 0.673) or who converted to DLB (0.21 6 0.09 cm2 vs. 0.20 6 0.06 cm2; mean difference of 0.0013 6 0.04 cm2; P 5 0.492).
Evolution of SN Echogenicity Over Time Of the 19 patients who had SN1 at baseline, repeated TCS showed SN1 in 14 (73.7%), insufficient bone window in in one (5.3%), and TCS was not done in four (21.1%) cases. None of the subjects who showed SN1 at baseline displayed SN- at the second evaluation (Table 2, Fig. 2). Of the four patients who
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FIG. 1. Baseline transcranial sonography findings of patients who underwent the follow-up examination.
changed from SN- to SN1 at the second assessment, two remained disease free, one developed PD, and one developed DLB.
Relationship Between TCS Results and Clinical Status Of the 11 patients with baseline SN- who developed a synucleinopathy, repeated TCS examination could be done in 10 individuals, showing SN- in eight (80%) and a change to SN1 in two (20%). Among the 33 subjects that were disease-free at the second assessment, 21 (63.6%) had SN-, 10 (30.3%) had SN1, and two (6.1%) had insufficient bone window at baseline. At the second evaluation, 16 (48.5%) still had SN-, 10 (30.3%) had SN1, four (12.1%) had insufficient bone window, and three (9.1%) could not undergo TCS. Of the 21 patients that were diagnosed with a synucleinopathy, 11 (52.4%) had SN-, eight (38.1%) had
SN1, and two (9.5%) had insufficient bone window at the first assessment. At the second evaluation, eight (38.1%) had SN1, eight (38.1%) had SN-, two (9.5%) had insufficient bone window, and three (14.3%) did not undergo TCS because they were deceased.
TCS Results According to Type of Synucleinopathy Eleven patients, eight men and three women, were diagnosed with PD at the mean age of 76.1 6 5.8 years. Eight exhibited the akinetic-rigid motor subtype and three the mixed motor subtype. SN1 was detected in four (36.4%) patients in the first evaluation and in four (36.4%) in the second assessment, all but two with the akinetic-rigid motor subtype. SN1 was unilateral in two patients and bilateral in three. Five (45.5%) patients had SN- in the baseline evaluation and three (27.3%) in the later examination.
TABLE 2. Transcranial sonography findings at the initial and second examinations TCS Results at Second Examination TCS Results at Initial Examination
SN1 (n 5 19) SN2 (n 5 32) Lack of bone window (n 5 4)
SN1 (n 5 18)
SN- (n 5 24)
Lack of Bone Window (n 5 6)
Not Performed (n 5 7)a
14 (73.7%) 4 (12.5%) 0
0 24 (75%) 0
1 (5.3%) 1 (3.1%) 4 (100%)
4 (21.1%) 3 (9.4%) 0
TCS, transcranial sonography; SN1, hyperechogenicity of substantia nigra; SN-, normoechogenicity of substantia nigra. a Reasons for not performing TCS at second assessment were death (n 5 5), unable to participate (n 5 1) and lost during follow-up (n 5 1).
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FIG. 2. Baseline and follow-up transcranial sonography findings according to clinical status at follow-up examination.
Insufficient bone window was seen in the same two patients at both TCS evaluations. Two PD patients died before the second TCS examination. Nine men were diagnosed with DLB at the mean age of 73.9 6 5.5 years. SN1 was detected in four (44.4%) patients in both examinations. SN1 was unilateral in two patients and bilateral in two. SN- was seen in five subjects in the first evaluation (55.6%) and in four (44.4%) in the follow-up evaluation. One patient who showed SN1 died before the second TCS examination. A 75-year-old woman was diagnosed with MSA and exhibited SN- at both assessments. The IRBD subject who was unable to undergo repeated TCS had SN- at baseline. The patient who was lost had SN1 at baseline. Among the two cases that died with the diagnosis of IRBD during the follow-up, one had SN1 and the other had SN- at baseline.
Discussion To the best of our knowledge, this is the first prospective longitudinal study evaluating TCS in IRBD. We have found that SN1 by itself is not a marker for the development of PD and other synucleinopathies after 5 years of close clinical follow-up. Because we previously found that the combination of decreased striatal dopamine transporter uptake and SN1 identified the early conversion to a synucleinopathy,16
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investigating whether dopamine transporter imaging is able to identify this same risk independently might be advisable. The area of the echogenicity of the substantia nigra did not change with time in IRBD, even in those patients who converted to PD. Most of the patients who had SN- at baseline and later developed a synucleinopathy had this same echo feature at the second assessment. No significant differences were seen between the first and second TCS examinations in the mean size of the substantia nigra and in the percentage of patients with SN1. These findings were disclosed for the whole IRBD cohort and also for the subgroup of patients who developed PD. Thus, the size of the substantia nigra, as assessed by serial TCS, does not reflect disease progression during the course of the prodromal phase of PD in subjects with IRBD. Most subjects with IRBD are eventually diagnosed with PD, DLB, and MSA.12-14 Thus, IRBD seems to be a suitable population for testing disease-modifying therapies in future clinical trials. For the design of such trials, finding a marker capable of identifying subjects with a high risk for the early development of parkinsonism and dementia, and also monitoring disease progression, showing longitudinal changes over time, are important. Available data in IRBD indicate that the combinations of SN1 plus decreased striatal dopamine transporter uptake16 and hyposmia plus color vision loss21 are strategies that identify subjects
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with an increased risk of developing a synucleinopathy after 2.5 and 5 years of follow-up. In IRBD, serial dopamine transporter imaging shows progressive decline in striatal tracer binding.22 In contrast, olfaction and color vision functions do not worsen with time in IRBD.21,23 In the current study, we have shown that for future disease-modifying trials in IRBD, TCS by itself is not useful because it does not identify patients at high risk for the development of a synucleinopathy and because it does not show changes in echo size with time. SN1 is found in 8% to 16% of healthy adults and constitutes an established risk maker for PD.24-29 A prospective population-based study involving 1,261 healthy people older than 50 years showed that SN1 is associated with a 20-fold increased risk to develop PD within the next 5 years, with a positive predictive value of 6.5%.6 Our study in IRBD showed that the SN1 relative risk for incident PD was only 1.42, whereas the positive predictive value was 22.2%. This positive predictive value of SN1 for PD in IRBD is higher than in the general population older than 50 years (22.2% vs. 6.5%) within the same 5-year period of observation.6 This might be explained by the fact that IRBD is per se a much stronger risk factor for PD than age in the general population. The occurrence of PD in our IRBD cohort after a 5-year observational period far exceeds the prevalence of PD in the general population of similar age (20% versus 2%).30 In PD, enlarged echogenic substania nigra occurs in approximately 90% of patients and is thought to reflect increased iron deposition and microglial activation within the substantia nigra.1 SN1 in PD is not a marker of progressive nigral degeneration, because it is neither associated with severity of parkinsonism4,5,31,32 nor with the degree of dopaminergic deficit detected by functional neuroimaging,24-26 and the size of the echogenic area is stable in the course of disease in spite of clinical disease progression.7,8 In our study, 11 patients were diagnosed with PD at the mean age of 76 years, and most showed the akinetic-rigid motor subtype. Among the seven PD patients who had sufficient acoustic temporal bone window at the second assessment, the size of the substantia nigra was stable, and three (43%) subjects had SN-. We do not know the reason for this relatively high percentage of SN- found in our PD sample. This result might be related to the small size of our cohort. Alternatively, a possible explanation is that these PD subjects (in whom RBD preceded parkinsonism) constitute a subtype of the disease in which normoechogenicity is more common. As we noted in our sample, PD patients in whom RBD antedates motor signs are characterized by older age at disease diagnosis (at approximately 72-74 years) and the akinetic-rigid motor subtype.12-14 A higher proportion of SN- may be one of the characteristics in this specific PD subgroup. Of note, studies in PD have shown that
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SN- is associated with older age at disease onset31 and that smaller substantia nigra echogenic size correlates with older age at PD onset.29 SN1 has also been reported in DLB in one study involving 14 subjects in which SN1 had a similar prevalence as in PD.34 In contrast, SN1 is not common in MSA.35,36 In our study, nine men were diagnosed with DLB, and SN1 occurred in approximately half of the cases, whereas SN1 was absent at both examinations in the only patient who developed MSA. Some limitations should be noted. First, the size of our cohort was somewhat small, and this can influence further evaluations in the follow-up. Second, at the end of the study, 60% of the individuals remained diseasefree. Longer follow-up with higher conversion rate will be required to confirm the results of our study. Finally, sonographic assessment of the substantia nigra was not possible in 8% to 12% of our sample because of insufficient temporal bone window. Strengths of this study are that most (87%) of the patients underwent a second TCS examination, the sonographer was blinded and used the same TCS machine and adjustments at both examinations, and high intrarater reproducibility, which indicates low variability and optimal reliability in our substantia nigra measurements. In summary, our study shows that TCS alone is not helpful in identifying those subjects who will convert to PD or a synucleiopathy within a 5-year period, and that serial TCS cannot be used to monitor the degenerative process within the substantia nigra during the prodromal stage of PD.
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