Abstract
Introduction
Response to drug withdrawal in patients with suspected drug‐induced parkinsonism (DIP) is of prognostic and therapeutic importance, but cannot be predicted solely on clinical information. The aim of this study was to validate SN hyperechogenicity (SN+) assessed by transcranial sonography as a predictor of response to drug withdrawal in this group of patients.
Methods
Patients were diagnosed according to previously published criteria and prospectively included in the study. All patients were followed until complete recovery of parkinsonian symptoms or at least for 6 months after discontinuation of the offending drug and then diagnosed as DIP or parkinsonism following neuroleptic exposure (PFNE). Transcranial sonography (TCS) findings were compared with the clinical diagnosis.
Results
Sixty patients comprised the group for the final analysis. Sixteen patients were classified as PFNE and 44 as DIP. The area of SN echogenicity was significantly increased in the PFNE group (0.23 cm2; standard deviation [SD]: 0.04), compared to the DIP group (0.14 cm2; SD, 0.05; one‐way analysis of variance; P < 0.001). Normal SN was significantly associated with complete recovery after withdrawal of the parkinsonism‐inducing drug (P < 0.0005). Accuracy of SN+ to distinguish PFNE from DIP was: sensitivity 81.2%; specificity 84.1%; positive predictive value 47.4%; and negative predictive value 96.2%.
Conclusions
We believe that SN+ assessed with TCS is a valid prognostic marker in the setting of suspected DIP. It is a nonexpensive, feasible technique that can be implemented for proper counseling and guidance of treatment decisions.
Keywords: transcranial sonography, drug‐induced parkinsonism, substantia nigra hyperechogenicity
Drug‐induced parkinsonism (DIP) is considered the most frequent cause of parkinsonism1 after idiopatic Parkinson's disease (PD), with an estimated prevalence of up to 3.3% in the elderly population.2, 3 Clinical signs, such as a symmetric syndrome, or concomitant tardive features, such as orofacial diskinesias and akathisia, are suggestive of DIP, but clinical assessment alone of a patient under a potentially parkinsonism‐inducing treatment cannot predict response to drug withdrawal.4 Up to 20% of patients might not improve, suggesting that the offending drug unmasked a preexisting subclinical neurodegenerative parkinsonism, most likely PD.5 Recognizing these patients is of importance for prognostic counseling, as well as for avoiding delays in beneficial treatment decisions.
Several markers increase diagnostic accuracy in the context of suspected DIP, mainly radiotracer‐imaging studies.6, 7 Single‐positron‐emission computed tomography and PET scans are available using several dopamine transporter (DAT) ligands.8 DAT uptake in the striatum is significantly decreased in PD patients, even during the early stages of the disease, because the motor symptoms do not appear until 60% to 80% of dopamine neurons degenerate.9 Drugs causing parkinsonism, such as dopamine blockers, have a very low affinity for DAT10; thus, DAT scans are useful for differentiating PD unmasked by drugs from DIP. However, these tests are costly and not always available.
Transcranial sonography (TCS) is as a less expensive and an available tool in the diagnostic workup of patients presenting with parkinsonian disorders.11, 12 SN hyperechogenicity (SN+) is defined as enlarged echogenic signal in the area of the SN and is present in at least 82% of PD patients and 10% of the healthy population.13, 14, 15, 16 Usefulness of TCS in PD diagnosis and differential diagnosis with atypical parkinsonism (with lower frequencies of SN hyperechogenicity and higher frequencies of lenticular hyperechogenicity and ventricular diameter abnormalities) is supported by a growing body of evidence in the last two decades.17 This biomarker is also associated with increased vulnerability of the nigrostriatal dopamine system and is considered a preclinical risk marker for PD.18, 19 Studies in psychiatric patients observed positive correlations between the SN echogenic area and the prevalence and severity of DIP.15, 20 For all these reasons, it has been argued that TCS could be helpful in detecting patients with DIP who have an underlying nigrostriatal dysfunction and are less likely to improve after withdrawal of the offending drug. This hypothesis has been previously explored with encouraging, but nonconclusive, results, probably owing to insufficient sample sizes.21, 22 In this study, we aimed to assess the accuracy of SN echogenicity measured with TCS to distinguish DIP from parkinsonism following neuroleptic exposure (PFNE),23 prospectively following the patients and observing their response to drug withdrawal.
Patients and Methods
Study subjects were recruited in the neurology outpatient clinics and movement disorders unit of a tertiary hospital (Hospital Universitario Ramón y Cajal, Madrid, Spain). Suspected DIP was considered when a potentially parkinsonism‐inducing drug had been started within 6 months of the onset of symptoms and taken for at least 6 months according to previously published diagnostic criteria.24 Subjects with previous PD or dementia diagnosis, those taking dopaminergic therapy, as well as those with overt signs of atypical parkinsonism were not included in the study. Also, those patients in which the treatment could not be discontinued were excluded. All dopamine receptor blockers and dopamine‐depleting agents were considered potentially parkinsonism‐inducing drugs, as well as other compounds known to produce parkinsonism through a less well‐known mechanism of action.25
TCS examinations and SN segmentations were performed by a single certified experienced ultrasound examiner, as previously described.11, 12 Clinical assessment was blinded to the ultrasound results and vice versa. A Toshiba Xario ultrasound system equipped with a 2.5‐MHz phased array transducer was used, following a standard protocol. Parameter settings used were a penetration depth of 15 cm, a dynamic range of 45 dB, and image brightness and time‐gain compensation adjustments as required.11, 26, 27, 28 The examination was performed bilaterally through the transtemporal bone window. In an axial midbrain plane, the ipsilateral SN was depicted as hyperechoic signals in the anterior part of the hypoechoic butterfly‐shaped midbrain. The image was frozen and zoomed, and the area of SN echogenicity was manually encircled. Three independent measurements were taken for each side. The measure of the higher area detected on the bilateral examination was used for the statistical analysis. The echogenicity of the midbrain raphe was also assessed bilaterally. In a diencephalic plane, the widths of the third and contralateral lateral ventricles (frontal horn) were measured, and the echogenicity of the contralateral basal ganglia was assessed semiquantitatively, as described earlier. SN+ was defined as an area ≥21 cm2 based on a receiver operating characteristic analysis between 105 PD subjects and 138 healthy controls, corresponding to the 90th percentile of the larger SN side of the healthy controls; full details are available in the complete reference.28
Patients with absent transcranial bone window were not included in the analysis.29 Patients lost to follow‐up or those who did not follow specific recommendations on drug withdrawal were not included in the final analysis. All the patients were asked to interrupt treatment with the parkinsonism‐inducing drug, referred to a neurosonology laboratory to undergo TCS, and followed up periodically until 6 months after the basal assessment, or until complete recovery. Patients achieving an improvement of 1 or 2 as measured by the Clinical Global Impression Improvement scale (CGI‐I) scale after drug withdrawal were considered to have DIP, whereas the others were included in the PFNE group. On the CGI, one query is rated on a 7‐point scale: “Compared to the patient's condition before drug withdrawal, this patient's condition is: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change from baseline; 5 = minimally worse; 6 = much worse; or 7 = very much worse since the withdrawal of the offending drug.” Clinical diagnosis was considered the gold standard for this study. Demographic and clinical characteristics were collected in the basal and final visits. Patients were assessed and rated at follow‐up by the same two independent movement disorder specialist. Hyposmia, depression, cognitive impairment, constipation, and rapid eye movement sleep behavior disorder (RBD) were assessed through a structured interview applied directly by the investigators to the patients. Motor asymmetry was defined as a difference of more than 2 points between right‐ and left‐side–specific sum scores on the UPDRS items 20 to 26. The protocol was approved by the local ethical committee. Written informed consent was obtained from all participants.
Statistical Analysis
The primary endpoint of the study was to explore the association between TCS findings and clinical improvement after withdrawal of the parkinsonism‐inducing drug. Association among clinical (motor, nonmotor, and demographic) variables and both clinical outcome and SN hyperechogenicity were secondary endpoints. Finally, diagnostic reliability of TCS for PFNE diagnosis in this setting was estimated.
A descriptive analysis was carried out using absolute and relative frequencies. Fisher's test or chi‐square were used for univariate comparisons, as appropriate. Analysis of variance (ANOVA) was used for quantitative variable comparisons. Bonferroni's correction was used to adjust the level of significance in multiple comparisons. In addition, diagnostic accuracy of midbrain hyperechogenicity for the diagnosis of neurodegenerative parkinsonism was calculated. All statistical analyses were carried out using SPSS software (version 14; SPSS Inc., Chicago, IL).
Results
Patients
Sixty‐seven patients with suspected DIP agreed to participate and signed the informed consent. One patient who was lost to follow‐up and 6 who did not have transcranial temporal bone window were excluded from the final analysis. A total of 60 patients who were finally included in the analysis (25 male; mean age: 73.3 ± 10.3 years) had been exposed to a mean of 1.3 parkinsonism‐inducing agents (range, 1–3) and mean exposure time of 16.22 months (±9.2 standard deviations [SDs]). The most frequently implicated drug was sulpiride (Table 1). Basal UPDRS‐III score was 26.9 (±11.1 SDs). The basal clinical and sonographic characteristics of the patients are listed in Tables S1 and Table 1.
Table 1.
List of offending drugs
| No. of Parkinsonism‐Inducing Agents | Name of Offending Drug(s) | Mechanism of Action | Total Subjects |
|---|---|---|---|
| 1 | Sulpiride | Dopamine blocker | 9 |
| Clebopride | Dopamine blocker | 8 | |
| Risperidone | Dopamine blocker | 4 | |
| Amiodarone | Class III antiarrhythmic | 3 | |
| Valproic acid | Anticonvulsant | ||
| Amlodipine | Calcium‐channel blocker | 2 | |
| Metoclopramide | Prokinetic | ||
| Tietilperazine | Dopamine blocker | ||
| Tetrabenazine | Dopamine depleter | ||
| Aripiprazole | Dopamine blocker | ||
| Levosulpiride | Dopamine blocker | ||
| Olanzapine | Dopamine blocker | 1 | |
| Quetiapine | Dopamine blocker | ||
| 2 | Clebopride and sulpiride | 2 | |
| Clebopride and tietilperazine | |||
| Clebopride and diltiazem | 1 | ||
| Clebopride and amlodipine | |||
| Levomepromacine and olanzapine | |||
| Clomipramine and fluoxetine | |||
| Abilify and quetiapine | |||
| Risperidone and quetiapine | |||
| Risperidone and amisulpiride | |||
| Paliperidone and valproic acid | |||
| Valproic and phenitonin | |||
| Amiodarone and sulpiride | |||
| Clomipramine (diazepam, valdoxan, denubil) | |||
| Amisulpiride and maprotiline | |||
| Sulpiride and tietilperazine | |||
| Metoclopramide and diltiazem | |||
| Maprotiline and betahistine | |||
| 3 | Amisulpiride, aripiprazol, and asenapine | 1 | |
| Tietilperazine, sulpiride, and amlodipine | |||
After a mean follow‐up of 10 months (±7.4 SDs), 16 patients (26.7%) with persistence or worsening of parkinsonism (CGI 3–7) were diagnosed as having PFNE, whereas 44 (73.3%) with complete or near complete recovery (CGI 1–2) were classified as DIP. Normal SN hyperechogenicity was significantly associated with clinical improvement (CGI 1–2; Fisher's test: P < 0.0005]. Area of SN echogenicity was significantly increased in the PFNE group (0.23 cm2; SD, 0.04), compared to the DIP group (0.14 cm2; SD, 0.05; one‐way ANOVA: P < 0.001; see Table 2; Fig. 1).
Table 2.
Demographic data, clinical data, TCS results, and diagnostic accuracy
| PFNE | DIP | PFNE vs. DIP | |
|---|---|---|---|
| Demographic and clinical data | |||
| Patients, n | 16 | 44 | |
| Female/male, n | 10/6 | 15/29 | 0.07 |
| Age, years; mean ± SD | 75.3 ± 6.8 | 72.5 ± 11.2 | 0.36 |
| Basal UPDRS III, mean ± SD | 27.1 ± 12.8 | 26.7 ± 10.5 | 0.9 |
| Final UPDRS III, mean ± SD | 26.7 ± 10.5 | 5.7 ± 4.3 | <0.001* |
| Tremor (n = 59), n (%) | 11 (68.7) | 28 (65.1) | 1.0 |
| Asymmetry (n = 59) (%) | 12 (75) | 17 (39.5) | 0.02 |
| Dyskinesia (n = 56) | 1 (6.25) | 7 (15.91) | 0.3 |
| Hyposmia (n = 56) (%) | 9 (60) | 7 (17.1) | 0.005* |
| RBD (n = 56) (%) | 7 (46.6) | 7 (17.1) | 0.036* |
| Depression (n = 59) (%) | 11 (68.7) | 29 (67.5) | 1.0 |
| TCS characteristics | |||
| SN max (cm2) | 0.23 ± 0.04 | 0.14 ± 0.05 | <0.001* |
| SN+, n (%) | 13 (81.2) | 7 (15.9) | <0.001* |
| IIIV (n = 56) | 7.4 ± 2.1 | 6.3 ± 2.0 | 0.08 |
| LV right side (n = 29) | 15.1 ± 2.1 | 16.8 ± 2.9 | 0.07 |
| LV left side (n = 26) | 15.1 ± 2.3 | 16.4 ± 2.4 | 0.18 |
| Raphe normal/discontinuous (n = 50) (%) | 10/5 (66.6/33.3) | 24/11 (68.6/31.4) | 1.0 |
| LN+ (n = 28) (%) no/yes/NA | 20/2/32 (90.9/9.1) | 8/2 (80/20) | 0.57 |
| CN+ no/yes (%) | 21/1 (95.5/4.5) | 10/0 (100/0) | 1.0 |
| Diagnostic accuracy (95% confidence interval) | |||
| Sensitivity, % | 81.2 (0.53–0.95) | ||
| Specificity, % | 84.1 (0.69–0.92) | ||
| PPV, % | 47.4** (0.40–0.83) | ||
| NPV, % | 96.2** (0.78–0.98) | ||
| Positive likelihood ratio | 5.11 (2.48–10.40) | ||
| Negative likelihood ratio | 0.22 (0.07–0.60) | ||
| TP, n | 13 | ||
| FP, n | 7 | ||
| FN, n | 3 | ||
| TN, n | 37 | ||
*Significance level: P < 0.05; **calculated for an estimated prevalence of PD of 15% among DIP according to previously published data. After Bonferroni's corrections for multiple comparisons, level of significance was set in α < 0.0045.
IIIV, third ventricle; LV, lateral ventricle; LN, lentiform nucleus; CN, caudate nucleus; TP, true positive; FP, false positive; FN, false negative; TN, true negative.
Figure 1.
Increased area of midbrain echogenicity in the PFNE group compared to the DIP group (P < 0.001; dotted line: value set at ≥0.21 cm2 to define hyperechogenicity according to previously published material).
SN+ was significantly associated not only with CGI 3 to 7 at the end of follow‐up, but also with male sex (chi‐square: P = 0.0003), whereas a borderline association with asymmetry in clinical signs was ascertained (P = 0.0292). No significant association was found with age, family history of PD, or clinical features such as tremor, dyskinesia, basal UPDRS III score, or nonmotor symptoms. As for clinical outcome, CGI 3 to 7 (PFNE) was significantly associated with SN+, with a borderline significant association with asymmetry in clinical signs (P = 0.0204), hyposmia (P = 0.0055), and RBD (P = 0.0367; Table 2).
Sensitivity value of SN+ ascertained through TCS obtained for clinical diagnosis of PFNE was 81.25%, whereas specificity was 84.09%. Predictive values were calculated with an estimated prevalence of 15% underlying PD in possible cases of DIP according to published results. Positive predictive value (PPV) was 47.4% and negative predictive value (NPV) was 96.2%. Positive likelihood ratio was 5.11 and negative likelihood ratio was 0.22 (Fig. 2).
Figure 2.
Basal and final (pre‐ and postdrug withdrawal) UPDRS‐III scores among the PFNE and DIP groups.
Discussion
The underlying nature of SN+ is still uncertain. Increased echogenicity has been associated with increased tissue iron and enhanced microglial activation in postmortem studies.30, 31, 32 However, it is known that the extent of hyperechogenicity does not correlate with the degeneration of presynaptic dopaminergic nerve terminals in patients with PD and may reflect different pathogenic mechanisms.33 Also, midbrain hyperechogenicity seems to be a stable marker that does not change with aging whereas it is known that age is a major risk factor for DIP. All these can be considered limitations of TCS as compared to dopamine radiotracers. TCS also requires significant training and is currently not available at most movement disorder centers. However, it is a less expensive, more widely available and noninvasive free of radiation ancillary test that can be performed in the movement disorder clinics as a part of a comprehensive workup evaluation of patients presenting with parkinsonian syndromes. TCS has proven to be useful for PD diagnosis in routine clinical practice when performed by skilled sonographers and has a level A evidence supporting its role in detecting premotor PD and subjects at risk for this common neurodegenerative disorder.17 For this reason, we hypothesized that the technique might be useful in detecting patients with underlying dopaminergic degeneration, who would be at a higher risk of not improving after withdrawal of the parkinsonism‐inducing drug.
Our cohort of suspected DIP patients reflects the actual phenomenology of this disorder, with patients recruited from general neurology and movement disorders clinics, avoiding the severity bias of pharmacovigilance and reference unit studies. Female sex and older age were frequent. Dopamine‐blocking agents, mostly prescribed for nonpsychiatric morbidities (dizziness, vertigo, and gastrointestinal complaints) were the most common, and classical signs of DIP (symmetric, tremoric) were frequent. Severity was overall moderate and nonmotor symptoms common. As for clinical outcome after withdrawal, the final clinical diagnosis rates in our study are similar to those found in the literature, in which up to 20% of the patients suffer persistent parkinsonism after discontinuation of the offending drug. SN echogenicity ascertained by TCS showed a strong association with clinical outcome, especially when it fell into the normal range, with high specificity and an NPV over 96%. Only 10 of 60 patients (16; 6%) were not correctly classified according to TCS. The rate of false negatives was low (3 cases) and in line with previous series of TCS in PD patients.34 However, the rate of false positives (7 cases) was higher, resulting in a lower PPV. This is not surprising, given the frequency of this biomarker in the general population (10%, with an estimated PPV of 25% in healthy individuals), and the long premotor phase of PD, with multiple genetic and environmental factors influencing the progression of subclinical degeneration, and time (or age) being probably the most influencing factor in the conversion to motor symptoms of PD.35 Patients with DIP (defined by full recovery after the follow‐up period) and SN+ (false positives) have probably at a higher risk of developing PD and longer follow‐up periods may ascertain clinical conversion to PD. Taking all this into account, TCS in the clinical setting of possible DIP is probably most useful as a screening technique, with a high NPV to rule out underlying PD, but less predictable in the case of positive results. We consider that this complementary technique can be a part of the overall clinical assessment, but never a definite diagnostic tool, because we can give estimates on recovery rate in the setting of suspected DIP based on the presence of SN+, but never establish a final diagnosis of the underlying pathology by means of TCS.
A previous prospective study explored usefulness of TCS in suspected DIP setting.22 However, a lower sample size and the adoption of more complex sonographic criteria, including lenticular nucleus echogenicity (which, although relevant in atypical parkinsonism diagnosis, is questionably useful in this setting), surely limited their results. Nevertheless, it must be outlined that this study, despite the small sample, was able to estimate a high NPV of TCS in this setting (87.5%), near to our own estimates.
As in previous studies,36, 37 the combination of SN+ with clinical variables such as RBD, hyposmia, and motor asymmetry were associated with clinically defined neurodegenerative parkinsonism and might improve the discrimination between DIP and PFNE.
As for the limitations, observer bias is a possibility in this study, although efforts were made to control it: The measurements of echogenicity were performed by a sonographer who was not involved in the clinical diagnosis of the patients, which was established at the end of follow‐up, whereas sonographic assessment was performed basally. Another limitation of the study is that it was performed in a single center, limiting the conclusions to the characteristics of a certain bounded population.
In conclusion, TCS offers useful information for the day‐to‐day clinical practice improving prognostic counseling and adding an element of value helpful for early treatment decisions in the setting of suspected DIP. Further studies with longer follow‐up periods are required for the generalization of our high diagnostic reliability results.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
J.L.‐S.M.: 1A, 1B, 1C, 2C, 3A
A.A.‐C.: 1A, 1B, 1C, 2A, 2B, 3B
J.B.C.: 1C, 2C, 3B
N.G.B.: 1C, 2C, 3B
I.C.C.: 1C, 2C, 3B
A.F.M.: 1C, 2C, 3B
M.C.M.L.: 1C, 2C, 3B
J.M.V.: 1C, 2C, 3B
J.C.M.‐C.: 1C, 2C, 3B
Disclosures
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: J.L.L.‐S. has received travel grants from Lundbeck and Krka pharmaceuticals. A.A.C. has received travel grants and speaker honoraria from AbbVie and Lundbeck Pharmaceuticals. J.C.M.‐C. has received research support from Allergan, AbbVie, and Lundbeck, and travel grants and speaking honoraria from AbbVie, Italfarmaco, UCB, Lundbeck, and Allergan.
Supporting information
Table S1. Baseline characteristics of the sample mean ± SD (range).
Figure S1. Transcranial ultrasound images of mesencephalic brainstem with hyperechogenicity of the SN. Echogenic area of the left SN is encircled for measurement (0.23 cm2).
Figure S2. Transcranial ultrasound images of mesencephalic brainstem with normal (no hyperechogenic) SN. Echogenic area of the left SN is encircled for measurement (0.13 cm2).
Acknowledgments
The authors thank the patients and their families for their collaboration and kindness and Prof. Uwe Walter for his priceless help and training in the implementation of transcranial sonography in our centre. All the authors state that (1) they have had full access to the data, (2) they have the right to publish all the data, and (3) they have had the right to obtain independent statistical analyses of the data. Jose López‐Sendón takes responsibility for the integrity of the data and the accuracy of the data analysis.
Drs. López‐Sendón Moreno and Alonso‐Cánovas contributed equally to this article.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. de Lau LM, Giesbergen PC, de Rijk MC, Hofman A, Koudstaal PJ, Breteler MM. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 2004;63:1240–1244. [DOI] [PubMed] [Google Scholar]
- 2. Llau ME, Nguyen L, Senard JM, Rascol O, Montastruc JL. [Drug‐induced parkinsonian syndromes: a 10‐year experience at a regional center of pharmaco‐vigilance]. [Article in French]. Rev Neurol (Paris) 1994;150:757–762. [PubMed] [Google Scholar]
- 3. Wenning GK, Kiechl S, Seppi K, et al. Prevalence of movement disorders in men and women aged 50–89 years (Bruneck Study cohort): a population‐based study. Lancet Neurol 2005;4:815–820. [DOI] [PubMed] [Google Scholar]
- 4. Poewe W, Seppi K. Diagnosis of drug‐induced parkinsonism: can transcranial sonography make the difference? Eur J Neurol 2013;20:1429–1430. [DOI] [PubMed] [Google Scholar]
- 5. Lopez‐Sendon JL, Mena MA, de Yebenes JG. Drug‐induced parkinsonism in the elderly: incidence, management and prevention. Drugs Aging 2012;29:105–118. [DOI] [PubMed] [Google Scholar]
- 6. Diaz‐Corrales FJ, Sanz‐Viedma S, Garcia‐Solis D, Escobar‐Delgado T, Mir P. Clinical features and 123I‐FP‐CIT SPECT imaging in drug‐induced parkinsonism and Parkinson's disease. Eur J Nucl Med Mol Imaging 2009;37:556–564. [DOI] [PubMed] [Google Scholar]
- 7. Lorberboym M, Treves TA, Melamed E, Lampl Y, Hellmann M, Djaldetti R. [123I]‐FP/CIT SPECT imaging for distinguishing drug‐induced parkinsonism from Parkinson's disease. Mov Disord 2006;21:510–514. [DOI] [PubMed] [Google Scholar]
- 8. Scherfler C, Schwarz J, Antonini A, et al. Role of DAT‐SPECT in the diagnostic work up of parkinsonism. Mov Disord 2007;22:1229–1238. [DOI] [PubMed] [Google Scholar]
- 9. Poewe W, Scherfler C. Role of dopamine transporter imaging in investigation of parkinsonian syndromes in routine clinical practice. Mov Disord 2003;18(Suppl 7):S16–S21. [DOI] [PubMed] [Google Scholar]
- 10. Tolosa E, Coelho M, Gallardo M. DAT imaging in drug‐induced and psychogenic parkinsonism. Mov Disord 2003;18(Suppl 7):S28–S33. [DOI] [PubMed] [Google Scholar]
- 11. Walter U. How to measure substantia nigra hyperechogenicity in Parkinson disease: detailed guide with video. J Ultrasound Med 2013;32:1837–1843. [DOI] [PubMed] [Google Scholar]
- 12. Walter U, Behnke S, Eyding J, et al. Transcranial brain parenchyma sonography in movement disorders: state of the art. Ultrasound Med Biol 2007;33:15–25. [DOI] [PubMed] [Google Scholar]
- 13. Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol 2008;7:1044–1055. [DOI] [PubMed] [Google Scholar]
- 14. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K. Degeneration of substantia nigra in chronic Parkinson's disease visualized by transcranial color‐coded real‐time sonography. Neurology 1995;45:182–184. [DOI] [PubMed] [Google Scholar]
- 15. Berg D, Jabs B, Merschdorf U, Beckmann H, Becker G. Echogenicity of substantia nigra determined by transcranial ultrasound correlates with severity of parkinsonian symptoms induced by neuroleptic therapy. Biol Psychiatry 2001;50:463–467. [DOI] [PubMed] [Google Scholar]
- 16. Berg D, Steinberger JD, Warren Olanow C, Naidich TP, Yousry TA. Milestones in magnetic resonance imaging and transcranial sonography of movement disorders. Mov Disord 2011;26:979–992. [DOI] [PubMed] [Google Scholar]
- 17. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS‐ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease. Eur J Neurol 2013;20:16–34. [DOI] [PubMed] [Google Scholar]
- 18. Berg D, Becker G, Zeiler B, et al. Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 1999;53:1026–1031. [DOI] [PubMed] [Google Scholar]
- 19. Berg D, Seppi K, Behnke S, et al. Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37‐month 3‐center study of 1847 older persons. Arch Neurol 2011;68:932–937. [DOI] [PubMed] [Google Scholar]
- 20. Jabs BE, Bartsch AJ, Pfuhlmann B. Susceptibility to neuroleptic‐induced parkinsonism—age and increased substantia nigra echogenicity as putative risk factors. Eur Psychiatry 2003;18:177–181. [DOI] [PubMed] [Google Scholar]
- 21. Mahlknecht P, Stockner H, Kiechl S, et al. Is transcranial sonography useful to distinguish drug‐induced parkinsonism from Parkinson's disease? Mov Disord 2012;27:1194–1196. [DOI] [PubMed] [Google Scholar]
- 22. Olivares Romero J, Arjona Padillo A, Barrero Hernandez FJ, Martin Gonzalez M, Gil Extremera B. Utility of transcranial sonography in the diagnosis of drug‐induced parkinsonism: a prospective study. Eur J Neurol 2013;20:1451–1458. [DOI] [PubMed] [Google Scholar]
- 23. Erro R, Bhatia KP, Tinazzi M. Parkinsonism following neuroleptic exposure: a double‐hit hypothesis? Mov Disord 2015;30:780–785. [DOI] [PubMed] [Google Scholar]
- 24. Schrag A, Ben‐Shlomo Y, Quinn NP. Cross sectional prevalence survey of idiopathic Parkinson's disease and Parkinsonism in London. BMJ 2000;321:21–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Lopez‐Sendon J, Mena MA, de Yebenes JG. Drug‐induced parkinsonism. Expert Opin Drug Saf 2013;12:487–496. [DOI] [PubMed] [Google Scholar]
- 26. Bouwmans AE, Vlaar AM, Srulijes K, Mess WH, Weber WE. Transcranial sonography for the discrimination of idiopathic Parkinson's disease from the atypical parkinsonian syndromes. Int Rev Neurobiol 2010;90:121–146. [DOI] [PubMed] [Google Scholar]
- 27. Walter U, Dressler D, Wolters A, Probst T, Grossmann A, Benecke R. Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy. Neurology 2004;63:504–509. [DOI] [PubMed] [Google Scholar]
- 28. Alonso‐Canovas A, Lopez‐Sendon JL, Buisan J, et al. Sonography for diagnosis of Parkinson disease‐from theory to practice: a study on 300 participants. J Ultrasound Med 2014;33:2069–2074. [DOI] [PubMed] [Google Scholar]
- 29. Wijnhoud AD, Franckena M, van der Lugt A, Koudstaal PJ, Dippel ED. Inadequate acoustical temporal bone window in patients with a transient ischemic attack or minor stroke: role of skull thickness and bone density. Ultrasound Med Biol 2008;34:923–929. [DOI] [PubMed] [Google Scholar]
- 30. Berg D, Roggendorf W, Schroder U, et al. Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 2002;59:999–1005. [DOI] [PubMed] [Google Scholar]
- 31. Berg D. Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease. J Neural Transm 2011;118:453–461. [DOI] [PubMed] [Google Scholar]
- 32. Berg D, Godau J, Riederer P, Gerlach M, Arzberger T. Microglia activation is related to substantia nigra echogenicity. J Neural Transm 2010;117:1287–1292. [DOI] [PubMed] [Google Scholar]
- 33. Spiegel J, Hellwig D, Mollers MO, et al. Transcranial sonography and [123I]FP‐CIT SPECT disclose complementary aspects of Parkinson's disease. Brain 2006;129(Pt 5):1188–1193. [DOI] [PubMed] [Google Scholar]
- 34. Berg D, Behnke S, Walter U. Application of transcranial sonography in extrapyramidal disorders: updated recommendations. Ultraschall Med 2006;27:12–19. [DOI] [PubMed] [Google Scholar]
- 35. Berg D. Substantia nigra hyperechogenicity is a risk marker of Parkinson's disease: yes. J Neural Transm 2011;118:613–619. [DOI] [PubMed] [Google Scholar]
- 36. Iranzo A, Lomena F, Stockner H, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid‐eye‐movement sleep behaviour disorder: a prospective study [corrected]. Lancet Neurol 2010;9:1070–1077. [DOI] [PubMed] [Google Scholar]
- 37. Busse K, Heilmann R, Kleinschmidt S, et al. Value of combined midbrain sonography, olfactory and motor function assessment in the differential diagnosis of early Parkinson's disease. J Neurol Neurosurg Psychiatry 2012;83:441–447. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Baseline characteristics of the sample mean ± SD (range).
Figure S1. Transcranial ultrasound images of mesencephalic brainstem with hyperechogenicity of the SN. Echogenic area of the left SN is encircled for measurement (0.23 cm2).
Figure S2. Transcranial ultrasound images of mesencephalic brainstem with normal (no hyperechogenic) SN. Echogenic area of the left SN is encircled for measurement (0.13 cm2).