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The Cerebellum ISSN 1473-4222 CerebellumDOI 10.1007/s12311-014-0642-8

Substantia Nigra Echogenicity inHereditary Ataxias With and WithoutNigrostriatal Pathology: a Pilot Study

Patricia Martínez-Sánchez, RubénCazorla-García, Irene Sanz-Gallego,Elisa Correas-Callero, Irene Pulido-Valdeolivas, et al.

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ORIGINAL PAPER

Substantia Nigra Echogenicity in Hereditary AtaxiasWith and Without Nigrostriatal Pathology: a Pilot Study

Patricia Martínez-Sánchez & Rubén Cazorla-García &

Irene Sanz-Gallego & Elisa Correas-Callero &

Irene Pulido-Valdeolivas & Javier Arpa

# Springer Science+Business Media New York 2015

Abstract Our objective was to determine whether substantianigra (SN) hyperechogenicity is greater in spinocerebellarataxias (SCA) with nigrostriatal affectation than in ataxiaswithout it. A cross-sectional case-control study analyzing fourgroups of patients was conducted: 1) nigrostriatal ataxias(SCA3 and SCA6), 2) nigrostriatal healthy controls matchedby age and sex, 3) non-nigrostriatal ataxias (FRDA andSCA7), and 4) non-nigrostriatal healthy controls matched byage and sex. All the patients underwent a transcranial ultra-sound performed by an experienced sonographer blinded tothe clinical, genetic, and neuroimaging data. The SN area wasmeasured and compared in the four groups. The SN area wasalso correlated with clinical features and genetic data in thetwo ataxia groups. We examined 12 patients with nigrostriatalataxia (11 SCA3 and 1 SCA6), 12 nigrostriatal healthy controlpatients, 7 patients with non-nigrostriatal ataxia (5 FRDA and2 SCA7), and 7 non-nigrostriatal healthy control patients. Themedian (IQR) SN area (cm2) was greater in the nigrostriatalataxias compared with the controls (right SN, 0.43 [0.44] vs.0.11 [0.25]; P=0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16]; P=0.001), but was similar among the non-nigrostriatal ataxiasand controls. Therewere no statistically significant differencesin the SN area between the nigrostriatal and non-nigrostriatalataxias, although there was a tendency for a greater left SNarea in the nigrostriatal compared with the non-nigrostriatalataxias (0.32 [0.25] vs. 0.16 [0.24], P=0.083). SNechogenicity is markedly greater in ataxias with nigrostriatal

pathology than in controls. The role of SN hyperechogenicityin differentiating ataxias with and without nigrostriatal pathol-ogy should be elucidated in future studies.

Keywords Substantia nigra . Echogenicity . Hereditaryataxias . Nigrostriatal pathology

Introduction

Transcranial sonography (TCS) studies have reportedhyperechogenicity of the substantia nigra (SN) in extrapyra-midal movement disorders such as Parkinson’s disease (PD),suggesting that SN hyperechogenicity indicates a vulnerabil-ity of the nigrostriatal system [1]. The mechanisms that con-tribute to this hyperechogenicity of the SN are not completelyunderstood but are thought to involve abnormal iron accumu-lation [2–4], decreased neuromelanin [4], and activation ofmicroglia [5].

SN hyperechogenicity is a frequent finding inspinocerebellar ataxias (SCA), which more frequently dem-onstrate extrapyramidal motor symptoms such as SCA type 2and type 3 (Machado Joseph disease) [6–13]. These twoataxias have demonstrated loss of SN cells in pathologicalstudies [14–17]. More recently, parkinsonian features havealso been described in patients with SCA6 [18, 19], andpostmortem studies have shown a widespread affection ofextracerebellar structures that includes neurodegeneration ofthe dopaminergic pars compacta of the SN [20].

Patients with SCA7, however, do not show parkinsonism,and other extrapyramidal symptoms are rare [18]. Further-more, there is no SN impairment in pathological studies of

P. Martínez-Sánchez (*) :R. Cazorla-García : I. Sanz-Gallego :E. Correas-Callero : I. Pulido-Valdeolivas : J. ArpaDepartment of Neurology and Stroke Center, La Paz UniversityHospital, Autonoma of Madrid University IdiPAZ Health ResearchInstitute, Paseo de la Castellana 261, 28046 Madrid, Spaine-mail: patrindalo@hotmail.com

CerebellumDOI 10.1007/s12311-014-0642-8

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patients with SCA7 [21]. Extrapyramidal symptoms are alsorare in Friedreich’s ataxia (FRDA), and its neuropathologicallesions do not affect the SN [22–25]. Previous studies haveshown that SN hypoechogenicity is more frequent in FRDApatients compared with controls [26–28], although no studyhas confirmed this [29].

We hypothesize that SN hyperechogenicity is greater inataxia patients with nigrostriatal affectation (nigrostriatalataxias: SCA3 and SCA6) compared with healthy controlsand with other ataxias without nigrostriatal affectation (non-nigrostriatal ataxias: FRDA and SCA7), as demonstrated byprevious pathological and neuroimaging studies. Our objec-tive was to determine the SN area by TCS in nigrostriatalataxias, non-nigrostriatal ataxias, and their correspondingcontrols.

Methods

A cross-sectional case-control study was conducted with fourgroups of patients: 1) nigrostriatal ataxias group: clinical andmolecularly proven SCA3 and SCA6, 2) nigrostriatal healthycontrol group: healthy subjects with no personal or familyhistory of parkinsonism or other movement disorder matchedfor age and sex, 3) non-nigrostriatal ataxias group: clinicallyand molecularly proven FRDA and SCA7, and 4) non-nigrostriatal healthy control group: healthy subjects with nopersonal or family history of parkinsonism or other movementdisorders matched for age and sex. All the subjects underwentthorough clinical and neurological examinations.

The variables studied included the following: age; sex; ageat disease onset; disease duration; the Scale for the Assess-ment and Rating of Ataxia (SARA) [30]; extrapyramidalsigns: rigidity, dystonia, extrapyramidal tremor, bradykinesia;other signs: hyperreflexia, hyporeflexia, Babinski sign,hypoesthesia; the Rapid Eye Movement (REM) Sleep Behav-ior Disorder Screening Questionnaire (RBDSQ) [31]; thepresence of restless leg syndrome (RLS) according to theInternational RLS Study Group criteria [32]; and the mini-mental state examination by Folstein [33]. The number ofCAG(n) expansions in the corresponding genes of patientswith SCA3, SCA6, and SCA7, as well as the number of GAAtriplet repeats in FRDA, were recorded.

Transcranial Sonography

All the subjects underwent a TCS performed through thetemporal acoustic bone window on both sides by applying aphased-array ultrasound system (Viamo, Toshiba®, Japan)equipped with a 5–1 MHz transducer (PST-25ST) using afrequency of 2.5 MHz, a penetration depth of 14–16 cm,and a dynamic range of 45–55 dB; image brightness andtime-gain compensation were adapted as necessary. Within

the butterfly-shaped structure of the mesencephalic brainstem,the SN ipsilateral to the ultrasound probe was identified in theB-mode setting and stored. Based on the recommendations ofa consensus paper byWalter et al. [34], the TCS examinationswere performed by an experienced sonographer (P M-S)blinded to the patients’ clinical, genetic, and neuroimagingdata. The echogenic signal at the anatomical site of the SNwas planimetrically encircled manually using computer-basedanalysis (NIHS ImageJ 1.46 program, developed at the USNational Institutes of Health and available on the Internet athttp://rsb.info.nih.gov/ij/index.html) on digital randomizedanonymous TCS images. The SN areas were thenindependently measured by two of the authors (R C-G and EC-C) to establish interrater reproducibility and reliability usingCohen’s kappa index. Considering the SN area value of ≥0.20 cm as hyperechogenic [9, 10], the interrater K coefficientwas 0.83.

Data Analysis

The SN area was measured and compared in the four groupsand was correlated with clinical features and genetic data inthe two ataxia groups. The statistical analyses were performedusing SPSS package 20.0 for Windows (SPSS Inc., Chicago,IL, USA). The continuous variables were tested using theMann-Whitney and Kruskal-Wallis tests, and the categoricalvariables were analyzed using the chi-squared test. The Spear-man correlation coefficient was used to analyze the relation-ship between the SN area and the clinical continuous vari-ables. Both sides of the SN area as well as the minimum andmaximum of any side of each individual were analyzed. Thecutoff value of the maximum SN area distinguishing the ataxiapatients from the control patients was established using anROC curve. P values less than 0.05 were consideredsignificant.

This study was approved by the local institutional ethicscommittee, and all the participants signed a written informedconsent document.

Results

A total of 21 patients with ataxia were studied by TCS, two ofwhom (both SCA6) were excluded for an inappropriate tem-poral window. Nineteen patients with ataxia were definitivelyincluded in the study: 12 patients with nigrostriatal ataxia (11SCA3 and 1 SCA6) and 7 patients with non-nigrostriatalataxia (5 FRDA and 2 SCA7). In addition, 12 nigrostriatalhealthy control patients and 7 non-nigrostriatal healthy controlpatients were analyzed (Table 1).

The demographic and clinical data for the ataxia group isshown in Table 2. The non-nigrostriatal ataxia group was

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younger and had a lower age at disease onset than thenigrostriatal ataxia group; however, the latter had lowerMMSE scores. Furthermore, FRDA patients were significant-ly younger than SCA3 patients (median [IQR] 24 [4] vs. 48[28], P<0.0001). The median (IQR) of the CAG repeats was

69.5 (8) for SCA3. The SCA6 patient had 23 CAG repeats,and the two SCA7 patients had 34 and 50 CAG repeatsrespectively. One FRDA patient had >800 GAA repeats andthe other four had >500.

The median (IQR) SN area (cm2) for SCA3 was right SN0.37 [0.45] and left SN 0.31 [0.20], and for FRDA, it was rightSN 0.36 [0.25] and left SN 0.21 [0.18]. The two SCA7patients had a right SN of 0.15 and 0.09 and a left SN of0.08 and 0.01 respectively. The SCA6 patient had a right SNof 0.67 and a left SN of 0.50 cm2.

Figure 1 shows the right, left, maximum, and minimum SNarea in the four groups. The median (IQR) SN area (cm2) wasgreater in patients with nigrostriatal ataxia compared withtheir controls (right SN, 0.43 [0.44] vs. 0.11 [0.25], P=0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16], P=0.001). Therewere no differences in SN area between the nigrostriatal andnon-nigrostriatal ataxias, although there was a tendency for ahigher left SN and minimum SN area in the nigrostriatalcompared with the non-nigrostriatal ataxia (0.32 [0.25] vs.0.16 [0.24], P=0.083 for the left and 0.32 [0.25] vs. 0.16[0.19], P=0.056 for the minimum SN). The SN area amongthe non-nigrostriatal ataxias and their controls was similar(Fig. 1).

The analysis of the median (IQR) SN area (cm2) for eachataxia type showed that there were not statistically significantdifferences among any of them. There were statistically sig-nificant differences between SCA3 ataxias and their controls:(0.37 [0.45] vs. 0.12 [0.27], P=0.002 for the right SN; 0.31[0.20] vs. 0.12 [0.16], P=0.005 for the left; 0.31 [0.20] vs.0.05 [0.16], P=0.010 for the minimum; and 0.38 [0.24] vs.0.18 [0.15], P<0.0001 for the maximum SN). There were notstatistically significant differences between other ataxias typesand their controls.

The ROC analyses indicated that the SN echogenic areaswere excellent variables for differentiating patients withnigrostriatal ataxia from control patients. The optimal maxi-mum SN area cutoff for distinguishing patients for controlswas 0.27 cm2 with 75 % sensitivity and 83 % specificity. SNechogenicity did not significantly differentiate the patientswith nigrostriatal ataxia from the patients with non-nigrostriatal ataxia. Furthermore, the echogenicity was similarin non-nigrostriatal ataxia group and its controls.

Considering SN hyperechogenicity as an area ≥0.27, sub-jects were classified as normal, unilateral, and bilateral SNhyperechogenicity (Fig. 2). A total of 58.3 % of nigrostriatalataxia patients had bilateral SN hyperechogenicity comparedwith 0 % of their controls, 28.6 % of non-nigrostriatal ataxias,and 14.3 % of their controls (P=0.011).

There were no significant correlations between SN area,clinical data (SARA score, MMSE, and extrapyramidal signs)and genetic parameters (triplet expansion). Two SCA3 pa-tients with RLS had SN hyperechogenicity: one unilateraland the other bilateral.

Table 1 Demographic data and ataxia distribution

Variables Ataxia group(n=19)

Control group(n=19)

P

Demographic data

Age, median (IQR), years 41 (30) 41 (30) 0.729

Men, n (%) 10 (52.6) 10 (52.6) 1

Ataxia distribution

Nigrostriatal ataxias, n (%) 12 (63.1)

SCA3, n (%) 11 (57.9) NA NA

SCA6, n (%) 1 (0.05)

Non-nigrostriatal ataxias, n (%) 7 (36.8) NA NA

Friedreich’s ataxia, n (%) 5 (26.3) NA NA

SCA7, n (%) 2 (1) NA NA

Table 2 Demographic and clinical data according to the ataxia group

Variables Nigrostriatalataxiasa

(n=12)

Non- nigrostriatalataxiasb

(n=7)

P

Demographic data

Age, median (IQR), years 51.5 (26) 26 (4) 0.004

Men, n (%) 8 (66.7) 2 (28.6) 0.170

Age at disease onset,median (IQR), years

42.5 (24) 22 (13) 0.004

Disease duration, median(IQR), years

7.5 (5) 6 (10) 0.837

SARA, median (IQR), years 11.3 (6.5) 14.2 (8.5) 0.100

Extrapyramidal signs, n (%) 2 (16.7) 0 (0) 0.509

Rigidity, n (%) 2 (16.7) 0 (0) 0.509

Dystonia, n (%) 1 (8.3) 0 (0) 1

Extrapyramidal tremor,n (%)

1 (8.3) 0 (0) 1

Bradykinesia, n (%) 2 (16.7) 0 (0) 0.509

Other signs

Hyperreflexia, n (%) 5 (41.7) 2 (28.6) 0.656

Hyporeflexia, n (%) 5 (41.7) 5 (71.4) 0.350

Babinski sign, n (%) 4 (33.3) 2 (28.6) 1

Hypoesthesia, n (%) 6 (50) 5 (71.4) 0.633

REM sleep behaviordisorder, n (%)

0 (0) 0 (0) –

Restless leg syndrome, n (%) 2 (16.7) 0 (0) 0.509

MMSE, median (IQR) 33 (2) 35 (1) 0.013

SARA Scale for the Assessment and Rating of Ataxia, REM rapid eyemovement,MMSE mini-mental state examination (Folstein)a SCA 3 and SCA 6b Friedreich’s ataxia and SCA 7 patients

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Discussion

This is the first study that compares the SN echogenicity inataxias with previously demonstrated pathological affectation

of SN, ataxias without it, and healthy controls. Our study showsthat SN ismarkedly greater in nigrostriatal ataxias than in healthycontrols. However, our data does not confirm an expanded SNechogenicity in nigrostriatal vs. non-nigrostriatal ataxias.

Fig. 1 Substantia nigra area innigrostriatal ataxias, non-nigrostriatal ataxias, and thecontrol groups. a Right SN area:P=0.004 for comparisonsbetween the four groups;P=0.001 for comparisonsbetween the nigrostriatal ataxiasand their controls; P=0.120 forcomparison between thenigrostriatal and non-nigrostriatalataxias. Left SN area: P=0.020for comparisons between the fourgroups; P=0.001 for comparisonsbetween the nigrostriatal ataxiaand its controls; P=0.083 forcomparison between thenigrostriatal and non-nigrostriatalataxias. b Maximum SN area:P=0.022 for comparisonsbetween the four groups;P=0.003 for comparisonsbetween the nigrostriatal ataxiasand their controls; P=0.142 forcomparisons between thenigrostriatal and non-nigrostriatalataxias. Minimum SN area:P=0.002 for comparisonsbetween the four groups;P<0.0001 for comparisonsbetween the nigrostriatal ataxiasand their controls; P=0.056 forcomparison between thenigrostriatal and non-nigrostriatalataxias. P>0.500 for allcomparisons between the non-nigrostriatal ataxia and its controls

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Previous studies have analyzed the SN echogenicity insome types of ataxia with parkinsonism [8–10]. Postert et al.[9] showed than SN hyperechogenicity (area ≥0.20 cm2) waspresent in 40 % of the 15 patients with SCA3 compared with13 % in the control patients. More recently, Pedroso et al. [10]reported SN hyperechogenicity (area ≥0.20 cm2) in 75 % ofthe 30 patients with SCA3 analyzed compared with 18 % inthe control patients. Similarly, in our nigrostriatal ataxia sam-ple, composed primarily of SCA3, 75 % presented SNhyperechogenicity (area ≥0.27 cm2) compared with 33 % oftheir controls. Furthermore, a recent study of patients withSCA2, another ataxia associated with parkinsonism, reportedSN hyperechogenicity in four of six patients (66 %) [8]. Thereare no previous studies analyzing the SN echogenicity inSCA6 patients. The only patient with SCA6 in our studyhad bilateral SN hyperechogenicity, which is congruent withthe spectrum of extrapyramidal features in this ataxia [18].

The significance of SN hyperechogenicity in ataxias withnigrostriatal affectation is unknown. Postmortem studies inpatients with PD and normal subjects have shown that SNhyperechogenicity is associated with a higher tissue iron level[3], decreased neuromelanin [4], and activation of microglia[5]. It had been suggested that SN hyperechogenicity reflectedearly nigrostriatal impairment, which increased the vulnera-bility of nigrostriatal dopaminergic transmission, and thusincreased the risk of developing parkinsonism [34, 35]. Thus,the presence of SN hyperechogenicity in patients with SCA3and SCA6 could be due to the high prevalence of parkinson-ism symptoms in these ataxias [18]. Recently, Pedroso et al.have shown that an increase in SN echogenic size in patientswith SCA3 correlates with presynaptic dopaminergicnigrostriatal dysfunction as measured by SPECT with[99mTc]-TRODAT-1, and they suggest a concurrent in vivopathophysiological mechanism [36]. A number of previouscross-sectional clinical TCS studies have reported that SNhyperechogenicity did not change in the course of PD, and itwas not related to clinical scores of motor impairment or to

disease duration, suggesting that such hyperechogenicity is atrait marker featuring the predisposition for the disease anddoes not reflect the extent of the underlying pathologicalprocess in the SN in a quantitative manner [34, 35]. Similarly,in the present study, SN hyperechogenicity did not correlatewith clinical or genetic data. Only 2 of our 12 nigrostriatalataxia patients showed extrapyramidal signs in the exhaustiveneurological exploration. It is possible that parkinsonian signscould bemasked by the predominant cerebellar dysfunction orthat pathological involvement of other brain nuclei mightabate parkinsonian signs, as has been suggested in a cohortof patients with SCA2 [8].

Regarding ataxias without parkinsonism, some studieshave analyzed SN echogenicity in patients with FRDA, withcontradictory results [26–29]. Whereas Synofzik el al. [26]and Stockner et al. [28] reported SN hypoechogenicity inFRDA compared with controls, Sierra et al. [29] did not findthis difference. Furthermore, SN hypoechogenicity appears tobe associated more with the concomitant presence of RSLthan with the FRDA itself [37]. It is believed that frataxindeficiency leads to an iron overload in the mitochondria and asubsequent accumulation of this metal in the affected organs.Accordingly, Synofzik et al. [27] showed hyperechogenicityof the cerebellar dentate nucleus in patients with FRDA;however, this possible hypoechogenicity remains to be con-firmed [29]. In the present study, the patients with FRDA hadsimilar SN echogenicity to the control patients and SN area ofthe same magnitude as SCA3 patients. The absence of RLS inpatients with FRDA could be an explanation. Moreover, theyounger age of FRDA patients, that usually is associated witha better temporal bone window, could be related to a better SNvisualization in this cohort. However, although the two pa-tients with SCA7 included in the study presented SNhypoechogenicity, there is no previous study to compare theseresults. In general, the non-nigrostriatal ataxia group (FRDA+SCA7) tended to have lower SN echogenicity than thenigrostriatal group. Future studies with a higher sample size

Fig. 2 Laterality of substantianigra hyperechogenicity.Percentage of subjects with anormal substantia nigra area(<0.27 cm2) and with unilateralor bilateral hyperechogenicity(area ≥0.27 cm2). P=0.058 forall comparisons. P=0.011 forcomparisons of bilateralhyperechogenicity among thefour groups. P=NS for othercomparisons

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are warranted to demonstrate whether SN echogenicity isuseful in distinguishing nigrostriatal from non-nigrostriatalataxias.

The primary limitation of the study is the smallsample size. The results, however, show a significant SNhyperechogenicity in patients with SCA3, confirming previousstudies. Our data also provide some clues as to theechogenicity of the SN in various types of ataxia, which hasnot yet been analyzed in the same work. Another limitation isthat the majority of the nigrostriatal ataxias group is composedby SCA3, preventing conclusions about SCA6. Furthermore,both in patients with ataxia and in control patients, the SN areameasures were slightly higher than in previous studies [6, 9,10, 29], but were similar in a more recent analysis [38]; this canbe explained by differences in ultrasound manufacture, trans-ducer properties, and improvements in ultrasound resolutionover time [38].

Conclusion

In conclusion, SN echogenicity is markedly greater in ataxiaswith nigrostriatal pathology than in controls. The role of SNhyperechogenicity in differentiating ataxias with and withoutnigrostriatal pathology should be elucidated in future studies.

Acknowledgments The authors thank Juliette Siegfried atServingMed.com for language editing of the manuscript. Dr. Arpa hasreceived grant funding for other projects from the Agencia Pedro LaínEntralgo (Madrid, Spain) and the Spanish Ministry of Health.

Conflict of Interest This project has been supported by a grant from theSpanish Ministry of Health, Social Policy and Equality (TRA-052). Theauthors declare no conflicts of interest.

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