Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; 15: 244–249
ORIGINAL ARTICLE
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Transcranial brainstem sonography as a diagnostic tool for amyotrophic lateral sclerosis
TINO PRELL1, ANNEKATHRIN SCHENK1, OTTO W. WITTE1,2, JULIAN GROSSKREUTZ1 & ALBRECHT GÜNTHER1,2 1Hans-Berger
Department of Neurology, Jena University Hospital, Jena, and 2Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany
Abstract Diagnosing amyotrophic lateral sclerosis (ALS) can be difficult, particularly in the early stage of disease; therefore, we evaluated the use of transcranial stem sonography (TCS) to improve early detection of the disease. In this crosssectional study, 94 patients with sporadic ALS and 46 age- and gender-matched healthy controls were evaluated by TCS according to a standardized protocol used to diagnose Parkinson’s disease. Approximately half (48%) of the patients with ALS showed a clear (⬎ 0.25 cm2) mesencephalic hyperechogenic structure, 20% showed a possible (⬍ 0.25 cm2) hyperechogenic structure and 24% patients showed no hyperechogenic structure in the brainstem. TCS findings were not correlated with gender, disease onset (spinal, bulbar), disease duration, ALSFRS-R scores, motor-evoked potentials and signal hyperintensities in conventional MRI. In 70% of the ALS patients these hyperechogenicities were found at the anatomical site of the substantia nigra. In terms of location and structure, hyperechogenicities in 30% of ALS patients were more heterogeneous than those in Parkinson’s disease with pronounced extensions both rostrally and laterally. In conclusion, although the neuropathological correlation to hyperechogenicity remains unclear, TCS is an easy, feasible and reproducible technique that could serve as an additional diagnostic tool and as a surrogate biomarker in ALS. Key words: Amyotrophic lateral sclerosis, substantia nigra, corticospinal tract
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration and death of motor neurons. While degeneration of the lower motor neurons can objectively be demonstrated by electromyographic examination or muscle sonography, involvement of the upper motor neuron, which is required to fulfil the El Escorial criteria for diagnosis of ALS, is often difficult to assess at early stages of the disease (1–3). Symptoms of lower motor neuron degeneration, such as progressive atrophic weakness, may obscure signs of upper motor neuron degeneration and contribute to the delay in diagnosis, initiation of riluzole therapy and potentially also enrolment into therapeutic trials (4). Upper motor neuron pathology is present in the primary motor and premotor cortex where Betz giant cells degenerate with signs of Golgi apparatus defragmentation, accumulation
of ubiquitin-positive inclusion bodies and signs of cytoskeletal pathology. Transcranial sonography (TCS) has evolved as a useful and widely applied technique for early differential diagnosis of Parkinson’s disease (PD). The typical hallmark for PD is hyperechogenic substantia nigra, which is found in 68%–99% of PD cases, depending on the ultrasound device and the applied cut-off values (5). Although extension of the hyperechogenic signal is not related to disease severity in PD, signal extension is usually largely contralateral to the more clinically affected side (5–8). In the current study, we used TCS in 94 patients with ALS to evaluate its applicability and reliability to improve diagnosis. Approximately half of the patients with ALS exhibited hyperechogenic structures in the brainstem. The results were correlated with clinical parameters, motor evoked potentials
Correspondence: T. Prell, Hans-Berger Department of Neurology, University Hospital Jena, Erlanger Allee 101, 07747 Jena, Germany. Fax: 49 3641 932 3452. E-mail:
[email protected] (Received 31 August 2013 ; accepted 6 January 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.881499
Brainstem sonography as tool for ALS (MEPS) and conventional magnetic resonance imaging (MRI) findings.
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Methods Ninety-four patients with ALS from University Hospital Jena (Jena, Germany) and 46 healthy controls were enrolled in the study from April 2010 to November 2012. ALS was diagnosed according to the revised El Escorial World Federation of Neurology diagnostic criteria by experienced ALS neurologists (JG,TP). All patients were receiving riluzole (2 ⫻ 50 mg/day) and none was receiving psychoactive drugs. Disability was assessed using the revised ALS functional rating scale (ALSFRS-R). Health related quality of life was assessed with the EQ-5D (http://www.euroqol.org). Patients with a history of PD, stroke or other neurodegenerative diseases were excluded. None of the patients showed classical Parkinsonian features, such as tremor, bradykinesia or rigor. All patients submitted written informed consent, and the study was approved by the local ethics committee. We used a high-end ultrasound machine (Siemens Accuson Antaris) equipped with a linear 1–4 Hz transducer in B-mode. TCS was performed for all patients with ALS according to a standardized protocol, by one skilled examiner blinded to the diagnosis. In brief, for the investigation, the patient was posed in the supine position, and the probe was placed at both temporal bone windows. A penetration depth of 14–16 cm and a dynamic range of 45–55dB were used to differentiate between the hypoechogenic, butterfly-shaped, midbrain structures and hyperechogenic basal cisterns. Automatic hyperechogenic size was calculated by manually encircling the outer hyperechogenicity circumference ipsilateral to the probe in the mesencephalic plane (9). Depending on the size of the hyperechogenic structures, we categorized these findings into three midbrain hyperechogenicity groups (‘clear’, ⬎ 0.25 cm2; ‘possible’, ⬍ 0.25 cm2 and ‘none’) to establish a simple and rapid system for routine clinical use. Furthermore, we did not want to exclude patients for whom the detection of a possible lesion could help in diagnosing ALS. MEPS and cerebral MRI were performed during routine clinical examinations at a maximum of 3–6 months before or after performing TCS. All data were analysed using PASW statistical software (base version 20; IBM, Armonk, NY, USA). All graphics and tables were designed using the Excel 2007 (Microsoft, Redmond, USA).
Results Study population The patient cohort included 94 patients with ALS and 46 age- and gender-matched healthy controls.
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The cohorts did not significantly differ in terms of age (p ⫽ 0.93) or male/female ratio. Mean disease duration in patients with ALS from the onset of limb weakness or bulbar symptoms was 25.9 ⫾ 31.2 months. The prevalent subtypes included 24.5% (n ⫽ 23) with bulbar and 75.5% (n ⫽ 71) with spinal onset. The mean ALSFRS-R score was 32.69 and mean EQ-5D score was 50.46. The disease duration (p ⫽ 0.95) and ALSFRS-R score (p ⫽ 0.52) did not differ between patients in the bulbar- and spinalonset groups. However, patients in the bulbar-onset group were significantly older (67.0 ⫾ 9.9 years) than those in the spinal-onset group (59.9 ⫾ 10.6 years; p ⫽ 0.005). Eighty-eight of 94 patients presented with clinical evidence of upper motor neuron involvement/degeneration. Eight patients had lower motor neuron dominant disease. Clinical characteristics of the patients are summarized in Table I. Prevalence of hyperechogenic midbrain structure Approximately half of the patients with ALS (n ⫽ 45, 47.9%) showed a clear hyperechogenic structure, whereas 19 (20.2%) showed a possible hyperechogenic structure and 23 (24.5%) had no hyperechogenic structures in the brainstem. Seven (7.4%) patients with ALS had an insufficient bone window. The patients showed two types of hyperechogenic structures: 1) In 70% of ALS subjects we observed lamellar structures, resembling hyperechogenic substantia nigra, indicating PD (Figure 1D, E). 2) In 30% of the cases we found plane structures that extended laterally and rostrally (Figure 1A, B). Therefore, in terms of location and structure, hyperechogenities in ALS were more heterogeneous than those in PD. The majority of patients with lower motor neuron dominant disease showed no hyperechogenic structures in the brainstem (88%, n ⫽ 7). In the patients group with a disease duration lower than 12 months, 19 patients (63.3%) showed a clear hyperechogenic structure, whereas four (13.3%) showed a possible hyperechogenic structure and six (20%) had no hyperechogenic structures in the brainstem. In the ALS group with a disease duration longer than 12 months, 26 patients (40.6%) showed a clear hyperechogenic structure, whereas 15 (23.4%) showed a possible hyperechogenic structure and 17 (26.6%) had no hyperechogenic structures in the brainstem. In the control group, one patient (2.2%) had a clear hyperechogenic structure, two (4.3%) had a possible hyperechogenic structure and 36 (78.3%) had no hyperechogenic structure in the brainstem (Figure 1F). Seven (15.2%) healthy controls had an insufficient bone window. Therefore, patients with ALS showed significantly more hyperechogenic changes in the brainstem compared with those in controls (p ⬍ 0.001). The sensitivity and specificity of TCS were 51.1% and 97.4%, respectively. The positive
246 T. Prell et al.
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Table I. Clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) and controls.
Number of patients, n Gender, n (%) Male Female Age (year), mean ⫾ SD (range) ALS subtype (onset) Bulbar, n (%) Spinal, n (%) Disease duration (months), mean ⫾ SD to fi rst symptoms (range) to initial diagnosis (range) ALSFRS-R totalscore, mean ⫾ SD (range) ALSFRS-R subscores, mean ⫾ SD subscore 1 – bulbar (range) subscore 2 – cervical (range) subscore 3 – lumbar (range) subscore 4 – thoracic (range) EQ-5d-VAS (%), mean ⫾ SD (range) width of the third ventricle (mm), mean ⫾ SD (range)
predictive value of TCS was 0.978. The width of the third ventricle was significantly larger in patients with ALS than that in the healthy controls (7.66 vs. 5.90 mm, respectively; Student’s t-test, p ⫽ 0.001).
ALS
Controls
94
46
52 (55.3) 42 (44.2) 61.60 ⫾ 10.87 6
27 (58.7) 19 (41.3) 61. 85 ⫾ 12.14 (34 – 81)
23 (24.2) 71 (74.7)
– –
25.94 ⫾ 31.19 (1–249) 14.50 ⫾ 25.66 (0 –210) 32.69 ⫾ 8.21 (16 – 46)
– – – – – – – – – – – – – – – – – 5.90 ⫾ 2.44 (1.9 –13.5)
p- value
0.856
8.55 ⫾ 3.37 (1–12) 7.02 ⫾ 3.23 (0 –12) 6.83 ⫾ 3.49 (1–12) 10.34 ⫾ 1.97 (5 –12) 50.64 ⫾ 20.69 (0 – 98) 7.66 ⫾ 2.86 (1.0 –14.1)
0.934
0.001
The width of the third ventricle did not differ significantly between the bulbar- and spinal-onset groups (8.38 vs. 7.46 mm, respectively; Student’s t-test, p ⫽ 0.246).
Figure 1. Transcranial sonography (TCS) patterns of midbrain axial sections from patients with amyotrophic lateral sclerosis (ALS), Parkinson´s disease (PD) and healthy controls. (A, B) In terms of structure and location, hyperechogenic midbrain changes in patients with ALS were more heterogeneous and different during the disease course. TCS of a patient with ALS taken in 2010 is shown in A and two years later in B. (C) Magnetic resonance imaging (MRI) showing hyperintensities along the corticospinal tract in a diffusion weighted image (DWI) (left) and T1-weighted image (right) in the same patient with ALS. (D) However, in ALS, hyperechogenities can also occur as tiny bands in the anatomic area of the substantia nigra. (E) A typical small patch of increased echosignal in PD marks the substantia nigra. Butterfly-shaped midbrain is outlined with a cursor for better visualisation. (F) TCS of a healthy control showed no remarkable hyperechogenic structure.
Brainstem sonography as tool for ALS
Table III. Comparison of transcranial sonography (TCS) with magnetic resonance imaging (MRI).
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Correlation with clinical data The results did not significantly differ between patients when they were stratified for gender (Pearson’s χ2 test; p ⫽ 0.42), disease duration (Kruskal-Wallis, p ⫽ 0.127), bulbar or spinal onset type (Pearson’s p ⫽ 0.33) or ALSFRS-R score (Kruskal-Wallis, p ⫽ 0.26). Regression analysis showed that hyperechogenic structures were not correlated to gender (p ⫽ 0.106, B ⫽ ⫺ 0.759), disease duration (p ⫽ 0.230, B ⫽ 0.033) or ALSFRS-R score (p ⫽ 0.443, B ⫽ 0.346). However, there were significant differences in age between the categorized groups (clear, possible and none; ANOVA, Tukey’s post hoc, p ⫽ 0.027). Regression analysis revealed that clear hyperechogenic structures were more frequently found in younger patients with ALS (p ⫽ 0.009, R ⫽ 0.061). There was no significant dependency between localization of the first signs of weakness on the right or left sides or bilaterally with the localization of hyperechogenic structures in the brainstem (right, left and bilateral; Fisher’s exact test, p ⫽ 0.127) and with the occurrence of hyperechogenic structure (clear, possible and none; Fisher’s exact test, p ⫽ 0.411). Comparison of TCS with MEPS In addition to TCS, MEPS were obtained during the routine diagnostic procedure in 76 patients with ALS. Magnetic stimulation enables non-invasive assessment of the functional integrity of the upper motor neurons by measuring the central motor conduction time (CMCT), which is the signal time from stimulation of the motor cortex to the lower motor neuron. Because CMCT is frequently abnormal in ALS (10), prolonged CMCT was observed in 60.6% (n ⫽ 57) of patients with ALS. Compared to TCS, MEPS were pathologically changed in 43.9% (n ⫽ 25) of patients with ALS with clear hyperechogenic structures, and 33.3% of patients with ALS with a normal brainstem had pathological MEPS (Table II). The sensitivity of TCS compared with that of MEPS was 43.9% and specificity was 50%. Changes in MEPS and TCS findings were not significantly correlated (Pearson’s p ⫽ 0.745). Comparison of TCS with MRI A total of 67 patients with ALS underwent conventional cranial MRI at our hospital, and 11.7% Table II. Comparison of transcranial sonography (TCS) with motor evoked potentials (MEPS). Pathological MEPS
Transcranial sonography Clear Possible No
247
Yes
No
25 (43.9%) 13 (22.8%) 19 (33.3%)
7 (50%) 4 (28.6%) 3 (21.4%)
Pathological MRI
Transcranial sonography Clear Possible No
Yes
No
7 (63.6%) 2 (18.2%) 2 (18.2%)
27 (48.2%) 13 (23.2%) 16 (28.6%)
(n ⫽ 11) of patients with ALS showed hyperintensities along the corticospinal tract (Figure 1C, Table III). The sensitivity of TCS compared with MRI was 63.6% and the specificity was 51.8%. Changes in MRI and TCS findings were not significantly correlated (Pearson’s p ⫽ 0.688). Discussion TCS is a useful and widely established technique for the differential diagnosis of PD and other neurodegenerative disorders. We detected abnormal hyperechogenic structures in approximately half of the patients with ALS in our cohort; however, this prevalence was lower than that in a recent TCS study of 86 patients with ALS (67%) or patients with PD (68%–99%) (5,12). The observed prevalence varies depending on three factors: 1) the definition of hyperechogenicity; 2) the ultrasound machine used and the quality of the temporal bone window; and 3) expertise of the investigator (11). The occurrence of these hyperechogenicities was not correlated to gender, disease duration, ALS onset type or disability (ALSFRS-R) (12). Therefore, TCS is probably not suitable to monitor disease progression. In contrast to the study by Fathinia et al., the width of the third ventricle was significantly larger in our ALS cohort than that in healthy controls, but it did not significantly differ between the bulbar- and spinal-onset groups (12). Of interest, observed hyperechogenicities were often detected more rostral to the substantia nigra, where the corticospinal tract is located. Moreover, hyperechogenicities frequently extended cranially (mesencephalic) and laterally, suggesting that hyperechogenic changes can differ between PD and ALS. Both the corticospinal tract and substantia nigra are known to be involved in ALS (13–16). Therefore, we compared our TCS findings with other methods, which are able to detect upper motor neuron disturbances in ALS. However, one has to take into account the methodological limitation that MEPS and conventional cranial MRI are not benchmark diagnostic methods for diagnosis of ALS. In ALS, CMCT is typically modestly prolonged, probably reflecting axonal degeneration of the fastest conducting corticomotoneuronal fibres and increased desynchronization of corticomotoneuronal volleys secondary to axonal loss (4). However, with a specificity of 30%–40% and a sensitivity of 60%–70%,
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248 T. Prell et al. MEPS alone are not sufficient for diagnosing ALS (17,18). The observed hyperechogenicities in TCS were not correlated with abnormal MEPS. Signal hyperintensities in conventional cranial MRI can be found in up to 75% of patients with ALS in T2-weighted and fluid attenuated inversion recovery (FLAIR) images along the corticospinal tract (19–24). However, these changes are not specific for ALS and do not correlate with clinical parameters (20,25–27). Furthermore, we found no correlation between signal alterations along the corticospinal tract and TCS findings. The lack of correlation between MEPS and MRI would indicate that the observed hyperechogenic structures do not reflect CST pathology. There is accumulating evidence that substantia nigra hyperechogenicity may also disclose a vulnerability of the nigrostriatal pathway in healthy persons (11). However, owing to the limited sensitivity and specificity of all three methods, this question cannot be definitely answered; thus, further studies are necessary to evaluate the neuropathological basis of the structural abnormalities observed in the brainstem of patients with ALS. A number of pathophysiological changes, known to occur in PD and ALS, can cause an increase in ultrasound reflection, such as enhanced iron levels, calcium disturbances, protein misfolding and aggregation and glial activation (11,28–32). As demonstrated, there are limitations to TCS. Besides an insufficient bone window in about 10% of elderly subjects, this method requires handling expertise to delineate brain structures (9). Although the ultimate nature of the observed hyperechogenic structures remains unclear (substantia nigra and/or corticospinal tract), we propose that TCS could serve as an additional tool in ALS because of its broad availability, short duration of investigation and low cost. This role of TCS should be studied by the comparison of ALS and ALS mimics. Another important issue is the question to which extent TCS could serve as surrogate biomarker for the intra-individual progression. In terms of its biomarker role, longitudinal studies of TCS in ALS patients are needed.
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Acknowledgement We thank the Department of Neuroradiology, University Hospital Jena for allocation of the MRI images. This study was undertaken in cooperation with the BMBF funded MND-NET.
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