Elsevier

The Lancet Neurology

Volume 7, Issue 5, May 2008, Pages 417-424
The Lancet Neurology

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The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study

https://doi.org/10.1016/S1474-4422(08)70067-XGet rights and content

Summary

Background

Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinson's disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made.

Methods

60 patients who presented with the first, but still unclear, clinical symptoms of parkinsonism had TCS in this prospective blinded study. Investigators were blinded to the results of the clinical investigations, the ultrasound findings, and the diagnosis at time of investigation. The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms. The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography (SPECT), or both.

Findings

A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients. At 12 months, 39 patients were clinically categorised as having iPD. Compared with endpoint diagnosis, the sensitivity of TCS at baseline was 90%7% and the specificity was 82·4%; the positive predictive value of TCS for iPD was 92·9% and the classification accuracy was 88·3%.

Interpretation

TCS is an easy to implement, non-invasive, and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes. The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier.

Funding

Michael J Fox Foundation for Parkinson's Research.

Introduction

The diagnosis of Parkinson's disease (PD) in the early stages and the differentiation of idiopathic Parkinson's disease (iPD) from atypical parkinsonian syndromes (aPS) is still a great challenge. The uncertainty of diagnoses based on clinical examination is evident in several studies. In a UK study, only 74% (298 of 402) of patients who received antiparkinsonian drugs fulfilled the UK Parkinson's Disease Society brain bank clinical diagnostic criteria for iPD: only 53% of the patients had a probable diagnosis of iPD,1 and in 21% of the patients the diagnosis of iPD was possible. Of the 800 patients with iPD who took part in the DATATOP (deprenyl and tocopherol antioxidative therapy for Parkinson's disease) study, the diagnosis had to be corrected in 8% (65 patients) after a mean of 6 (SD 1·4) years of follow-up. The reasons for changing the dignoses were additional clinical findings that suggested an aPS, atypical results in neuroimaging studies, or post-mortem findings.2 Similarly, in a post-mortem study of 100 patients who had a clinical diagnosis of iPD, histopathological features that are typical of iPD (ie, Lewy bodies) were found in only 76%.

Functional imaging methods, including PET with 11C-raclopride (RAC) and single-photon emission computed tomography (SPECT) with 123I-iodobenz-amide,3, 4 are useful for the differential diagnosis of PD and a range of aPS. However, functional neuroimaging does not enable a correct diagnosis to be made in all patients.5 Moreover, the broad application of these imaging methods to all patients, even those in the early stages of the disease, is limited by availability, costs, and the risks of giving radioactive tracers. Therefore, a method is needed that provides a morphological marker with high predictive values that can be applied without side-effects to a large number of patients to improve our ability to make an early and secure differential diagnosis. The results of various studies on different patient groups suggest that transcranial B-mode sonography (TCS) could be such a method. TCS has been used for more than 10 years to diagnose movement disorders such as PD,6, 7, 8 dystonia,9 Huntington's disease,10 Wilson's disease,11 and spinocerebellar ataxia.12

The characteristic ultrasound finding in patients with PD is an enlarged area of echogenicity in the area of the substantia nigra (SN), which is thought to be associated with increased iron concentrations.13, 14 This echofeature (figure 1) is detected with high sensitivity and specificity15 in more than 90% of patients with PD.6, 8, 16 Moreover, SN hyperechogenicity is a stable marker because the area of echogenicity is not related to the disease stage and did not change during the course of disease progression over a 5-year follow-up period.17

In retrospective studies the use of TCS has enabled the differentiation of iPD from aPS, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), at later stages, with high sensitivity and specificity.18, 19, 20, 21 The accuracy of the differential diagnosis can be enhanced by additional assessment of the echogenicity of the basal ganglia (BG); hyperechogenicity of the lentiform nucleus is commonly seen in patients with atypical parkinsonian syndromes (aPS), including MSA and PSP, whereas patients with iPD have this echofeature only rarely (figure 2).20, 22 However, up to now, there are no prospective data on the potential of TCS for the early and differential diagnosis of PD; therefore, we set out to determine, prospectively, in a blinded study, the predictive value of TCS for the early, differential diagnosis of PD versus aPS in patients for whom the first mild signs of parkinsonism had led to a consultation in our PD outpatient clinic.

Section snippets

Participants

Patients who presented for the first time at the PD outpatients' clinic of the University of Tübingen, Germany, between September, 2005, and August, 2006, with the early symptoms of mostly akinetic–rigid parkinsonism were investigated prospectively. Patients who presented with mostly rest tremor were not included, to avoid any bias due to this unconcealable clinical symptom. Only patients with temporal acoustic bone windows that enabled the identification of structures within the mesencephalic

Results

Figure 3 shows the trial profile. 60 patients (31 men and 29 women) of median age 65 years (IQR 36–81 years) who had early signs of slowness and rigidity indicative of a parkinsonian syndrome were enrolled on the basis that between a sixth and a quarter were estimated to develop the clinical picture of an aPS and the rest would develop PD. All patients who met the inclusion criteria during the study period were enrolled. The median time since the first signs of motor slowness or stiffness was

Discussion

The results of previous studies suggest that TCS has great potential to diagnose iPD and differentiate between aPS at the late stages.16, 18, 19, 20, 21, 22 In this prospective follow-up study we show that TCS is also valid for the diagnosis and differential diagnosis of iPD in the early stages. The non-invasiveness, broad availability, and low cost of TCS might give it an advantage over other neuroimaging methods that can diagnose iPD or distinguish it from aPS with comparable predictive

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