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© 2010 by the American Institute of Ultrasound in Medicine
J Ultrasound Med 29:37-42 • 0278-4297

Correlation Between Substantia Nigra Features Detected by Sonography and Parkinson Disease Symptoms

Petra Bártová, MD, PhD, David Skoloudík, MD, PhD, Pavel Ressner, MD, PhD, Katerina Langová, Roman Herzig, MD, PhD and Petr Kanovsky, MD, PhD

Department of Neurology, University Hospital Ostrava, Ostrava, Czech Republic (P.B., D.S.); Department of Neurology, Hospital Novy Jicín, Novy Jicín, Czech Republic (P.R.); and Institute of Biophysics (K.L.), and Department of Neurology (D.S., R.H., P.K.), Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.

Address correspondence to David Skoloudík, MD, PhD, Department of Neurology, University Hospital Ostrava, Tr 17, Listopadu 1790, CZ-708 52 Ostrava, Czech Republic. E-mail: skoloudik{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective. The aim of this study was to assess the correlation between substantia nigra (SN) echogenic features and area and the clinical symptoms in patients with Parkinson disease (PD). Methods. Clinical examinations and transcranial sonographic evaluations of the SN were performed in 115 consecutive patients with PD. The presence of tremors, rigidity, bradykinesia, gait disorders, speech disorders, and hypomimia was evaluated according to the motor portion of the Unified Parkinson Disease Rating Scale. The Mann-Whitney U test, the Kruskal-Wallis test, analysis of variance, and multivariate analysis were applied when assessing statistical significance. Results. An enlarged and hyperechoic SN existed in 84.0% of patients with bilateral rigidity but in only 70.6% of patients with unilateral rigidity (P < .05). Similarly, 85.0% of patients with bilateral bradykinesia in comparison with 65.7% of patients with unilateral bradykinesia had an enlarged and hyperechoic SN (P < .05). A significant correlation was shown between the SN echogenicity and area (r = 0.705; P < .01). Conclusions. An enlarged and hyperechoic SN seems to be a marker of structural involvement of the SN in patients with PD. This structural involvement is expressed more in patients with bilateral rigidity and bradykinesia.

Key Words: bradykinesia • Parkinson disease • substantia nigra • transcranial sonography • tremor

Abbreviations: ANOVA, analysis of variance • HY, Hoehn-Yahr • L-DOPA, L-3,4-dihydroxyphenylalanine • PD, Parkinson disease • SN, substantia nigra • TCS, transcranial sonography • UPDRS, Unified Parkinson Disease Rating Scale


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Transcranial sonography (TCS) can show structural changes in the substantia nigra (SN) of patients with Parkinson disease (PD).1–3 A hyper-echoic and enlarged SN can be detected in about 90% of patients with PD but only 8% to 14% of the general healthy population.4–8 Although previous studies have shown that enlargement of a hyperechoic SN is stable over time, the clinical observations did not exceed 5 years.9,10

Moreover, studies published so far have shown that TCS-detectable changes of SN echogenicity are not strictly specific only for PD, but they are also more frequent in other movement disorders than in the healthy population.2–4,7,11 An enlarged and hyperechoic SN can be detected in 9% to 50% of patients with multiple system atrophy,12–14 in 20% to 40% of patients with vascular parkinsonism,15,16 in 90% of patients with corticobasal degeneration,12,17 and in up to 97% of patients with Lewy body dementia.18

One can therefore hypothesize that increased echogenicity and enlargement of the SN are not strictly disease-specific markers but could be serve as markers of structural (probably neurodegenerative) changes of the SN. The aim of this study was to assess the correlation between the SN echogenicity and SN area and the character of clinical symptoms in patients with PD. A second aim was to correlate the SN hyperechogenicity and area as detected by TCS.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Over a 2-year period, clinical examinations and TCS evaluations of the SN were performed in 115 consecutive patients with PD (73 male and 42 female; mean age ± SD, 66.1 ± 11.8 years). The diagnosis of PD was established according to the diagnostic criteria of the Parkinson’s Disease Society Brain Bank of the United Kingdon.19,20 The Hoehn-Yahr (HY) stage was assigned in all patients. Inclusion criteria were HY stage 2 or 3 (72 patients with stage 2 and 43 with stage 3), a sufficient temporal bone window during TCS, and signed informed consent.

Clinical Examination
The presence of tremors, rigidity, bradykinesia, gait disorders, speech disorders, and hypomimia was assessed. Tremors, bradykinesia, and rigidity were examined and evaluated as unilateral (asymmetric) or bilateral (symmetric). These clinical findings, together with gait disorders and hypomimia, were classified according to subscale III (motor portion) of the Unified Parkinson Disease Rating Scale (UPDRS-III) in the "off" stage.20,21 The presence of clinical symptoms was rated unilateral (asymmetric) if a patient scored 0 or 1 for the corresponding item in UPDRS-III on one side and 2 to 4 on the opposite side in the off stage with unchanged medication for at least 2 months. The presence of clinical symptoms was rated bilateral (symmetric) if a patient scored 1 or 2 to 4 for the corresponding item in UPDRS-III on both sides. Patients who scored 0 on both sides for the corresponding item in UPDRS-III were classified as not having the clinical symptom.

Transcranial Sonographic Examinations
A 2- to 4-MHz P4-2 phased array transducer (HDI 5000; Philips Healthcare, Bothell, WA) was used for TCS examinations. The examination was performed through a temporal bone window with a penetration depth of 15 cm, a dynamic range of 50 dB, a thermal index of 1.9, and a mechanical index of 1.3. A butterfly-shaped structure consisting of the mesencephalic brain stem and the region of the SN was depicted as clearly as possible from the transverse plane. The right and then left temporal bone windows were used. Only the ipsilateral SN was evaluated.

The sonographic examinations were performed within 1 month after the clinical examinations (13 ± 7.4 days). All examinations were performed by a sonographer with more than 10 years of clinical experience. The sonographer was blinded to the diagnosis and symptoms of the studied patients. The right and then left temporal bone windows were used, and both images were saved in the JPEG format. Personal data and examination times were deleted, and all acquired images were encoded with a unique key. The SN echogenicity on a 5-grade scale6 and the SN area measurement from the VistaMatrix program (SkillCrest LLC, Chicago, IL) were evaluated on all images by a blinded rater (Table 1Go and Figure 1Go). The methods have been described in more detail previously.22 Substantia nigra echogenicity grades 3 through 5 were classified as hyperechoic, and an SN area of greater than 0.25 cm3 was classified as enlarged.


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  		Table 1. Evaluation of SN Echogenicity
 

Figure 1
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  		Figure 1. Measurement of the SN area by TCS: hyperechoic enlarged grade 3 SN; area, 0.59 cm3.

 
Statistical Evaluation
The following tests were applied when determining the statistical significance of the study. The Mann-Whitney U test, the Kruskal-Wallis test, and multiple comparisons were used to evaluate the correlation between the SN area and echogenicity, respectively, and the clinical symptoms, sex, HY stage, duration of PD symptoms, and duration of L-3,4-dihydroxyphenylalanine (L-DOPA) therapy.23 The Spearman rank correlation was used to evaluate the correlation between the SN area and echogenicity, respectively, and age. Analysis of variance (ANOVA) was used to evaluate the correlation between the SN area and echogenicity. Statistical evaluations were performed with SPSS version 14.0 software (SPSS Inc, Chicago, IL). All tests were performed with P < .05 considered statistically significant.

Ethics Committee Approval
The study was conducted in accordance with the Declaration of Helsinki (1975, revised 1983 and 2004) and was approved by the local Ethics Committee. All participants gave informed consent before inclusion in the study.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
During the 24-month study period, 125 consecutive patients with PD were screened. Ten of the patients (9%) were excluded because of an insufficient temporal bone window during the TCS examination. The characteristics of the 115 enrolled patients are shown in Table 2Go.


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  		Table 2. Patient Characteristics
 
The correlations between PD symptoms and SN echogenicity and area are presented in Table 3Go. Patients with bilateral rigidity and bilateral bradykinesia had significantly greater SN echogenicity and enlargement than patients with the unilateral presence of these symptoms. An enlarged and hyperechoic SN existed in 84.0% of patients with bilateral rigidity but in only 70.6% of patients with unilateral rigidity (P < .05). Similarly, 85.0% of patients with bilateral bradykinesia in comparison with 65.7% of patients with unilateral bradykinesia had an enlarged and hyperechoic SN (P < .05).


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  		Table 3. Correlation Between PD Symptoms and SN Echogenicity and Area (Mann-Whitney U Test)
 
Nonsignificant differences were found between the SN echogenicity and area in patients with unilateral or bilateral tremors, absence of tremors, gait disorders, speech disorders, and hypomimia (Table 3Go).

The SN echogenicity and area were not sex dependent (P > .1). A significant correlation was detected between age and the SN echogenicity and area, with Spearman rank correlations of r = 0.25 (P < .05) and r = 0.31 (P < .05), respectively. The SN area was also dependent on the HY stage (P = .006) but no correlation was detected between the SN echogenicity and HY stage (P = .23). There were also no correlations between the SN echogenicity and area and the duration of the disease, medications used, and duration of L-DOPA therapy.

Multiway ANOVA showed that the correlation between bilateral rigidity (P = .039) and bilateral bradykinesia (P = .002) and the SN area and echogenicity was independent of the HY stage, duration of the disease, and age. A subsequent correlation was found between the SN echogenicity and area (r = 0.705; P < .01; Figure 2Go) in this set of patients.


Figure 2
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  		Figure 2. Correlation between the SN echogenicity and area (ANOVA).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study showed a better correlation between bilateral rigidity, bilateral (symmetric) bradykinesia, and a hyperechoic and enlarged SN than unilateral (asymmetric) expression of these symptoms in patients with PD. The correlation between clinical symptoms and the SN area was suggested by Berg et al,7 who found a correlation between finger and foot tapping in UPDRS-III scores and a hyperechoic and enlarged SN in elderly participants without PD. On the other hand, in a study performed on patients with PD, Berg et al24 showed that a hyperechoic and enlarged SN occurred more frequently contralateral to the side with the more pronounced clinical symptoms.

However, the aim of our study was not only to compare the PD symptoms with SN findings and the asymmetry of the SN area but also to assess the correlation between the SN findings and the symmetry of the PD symptoms. An explanation for the correlation of the enlarged and hyper -echoic SN with bilateral rigidity and bilateral bradykinesia is only speculative. One can hypothesize that the structural involvement of the SN detectable by TCS is responsible for some symptoms in patients with PD. Nevertheless, the duration of the disease is another factor that could play an important role. The unilateral presentation of clinical symptoms occurs mainly at the beginning of the disease, and during disease progression, the symptoms become bilateral. This could be an explanation for the study results only in the cases of increasing SN echogenicity and area during the course of PD. The results of this study showed a significant correlation between the SN area and HY stage and also a slight correlation between the age and SN area and echogenicity, respectively. However, we did not confirm any correlation between the duration of the disease or duration of L-DOPA therapy and SN features, in concordance with previous studies.2,9,10

It is not known why the SN findings, as assessed by TCS, do not undergo any (or only minimal, TCS-undetectable) changes during the course of PD,2,3 even in cases of the fast progression of clinical symptoms. One could speculate that the correlation between the HY stage and SN area could be caused by a better response to therapy or slower progression of the disease in the patients with a smaller echogenic area in the SN. This has to be confirmed in future studies.

Walter et al2 conceded that only a very limited number of ultrasound systems were used in TCS studies that evaluated the SN until 2006. They assumed that the SN echogenicity and area could have varied in different ultrasound systems. That could be the reason for the larger measured SN area in some of our patients in comparison with previous studies.2 Nevertheless, the sensitivity, specificity, positive and negative predictive values, and even reproducibility of TCS evaluation of SN features in our previous studies6,16,22 were equal to those in other published studies.2–5,25

Berg et al25 showed that a hyperechoic and enlarged SN is induced by iron accumulation. However, it is still questionable whether any other factors could play a role here, eg, structural changes of neurons or glial cells (atrophy and morphologic changes of cells) in the SN caused by primary or secondary involvement of the brain stem, as in patients with a lacunar state. In these patients, increased echogenicity in the area of the basal ganglia caused by neuronal loss is detectable by TCS.26

In our previous study, we showed equal reproducibility of both the SN area and echogenicity.22 The results of this study (as shown in Figure 1Go) also confirm a substantial correlation between the SN echogenicity and area in patients with PD. That is why it seems preferable to evaluate both TCS parameters of the SN in future studies.

Several limitations of this study should be mentioned. First, an insufficient temporal bone window prevented performance of TCS examinations in 9% of the patients. Second, TCS evaluation of the SN depends on the sonographer’s experience. Few studies have confirmed that only experienced sonographers can achieve reproducible results.3,15 However, in this study, TCS was performed by a highly experienced sonographer and evaluated by a blinded rater. Third, technical limitations involving different levels of performance due to device technology have to be mentioned. An additional limitation was the small number of patients. This could have caused a study bias in combination with interindividual evaluation of patients’ clinical symptoms. Finally, an arbitrary classification of the unilateral (asymmetric) and bilateral presence of symptoms according to UPDRS-III was used.

In summary, a hyperechoic and enlarged SN detected by TCS significantly correlates with bilateral rigidity and bilateral bradykinesia in patients with PD. These results should be confirmed by future studies involving larger numbers of patients in different stages of PD. The background of SN changes as well as echogenicity changes of other various brain structures in patients with movement disorders and the correlation of SN changes on TCS with the clinical course of PD should be addressed in the future.


   Footnotes
 
Received August 6, 2009, from the Department of Neurology, University Hospital Ostrava, Ostrava, Czech Republic (P.B., D.S.); Department of Neurology, Hospital Novy Jicín, Novy Jicín, Czech Republic (P.R.); and Institute of Biophysics (K.L.), and Department of Neurology (D.S., R.H., P.K.), Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Revision requested September 12, 2009. Revised manuscript accepted for publication September 22, 2009.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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