We have aimed to assess whether muscle thickness ultrasound (US) shows differences between patients with chronic inflammatory demyelinating polyneuropathy (CIDP), chronic axonal polyneuropathy (CAP), and other neuromuscular (NM) diseases compared to controls and to each other.
Methods
We performed a cross-sectional study from September 2021 to June 2022. All subjects underwent quantitative sonographic evaluation of muscle thickness in eight relaxed muscles and four contracted muscles. Differences were assessed using multivariable linear regression, correcting for age and body mass index (BMI).
Results
The study cohort consisted of 65 healthy controls, and 95 patients: 31 with CIDP, 34 with CAP, and 30 with other NM diseases. Both relaxed and contracted muscle thickness in all patient groups were lower than in the healthy controls, after controlling for age and body mass index (BMI). Regression confirmed that the differences persisted between patient groups and healthy controls. Differences between patient groups were not apparent.
Conclusion
The current study shows that muscle ultrasound thickness is not specific in NM disorders, but shows a global reduction in thickness compared with healthy controls after corrections for age and BMI.
Ultrasound for muscle imaging is used for diagnostic and therapeutic purposes and to monitor disease progression.
The current study aimed to evaluate if muscle ultrasound (US) shows differences in patients with chronic axonal polyneuropathy (CAP), chronic inflammatory demyelinating polyneuropathy (CIDP), and other neuromuscular diseases (NM).
Muscle ultrasound thickness can differentiate neuromuscular disorders from healthy controls, after correction for age and BMI, but does not distinguish between different NM disorders.
Additional studies expanding the number and distribution of the muscles tested may enable differentiation of NM disorders.
Introduction
Polyneuropathy is a common neurological disorder affecting peripheral nerves, with an overall prevalence reported of 1–2.4% in the general population and 7–8% in the older population [1, 2]. Disorders of peripheral nerves and muscles have been traditionally evaluated through a combination of history-taking, clinical examination, and electrodiagnostic studies (nerve conduction studies and electromyography) [3]. Ultrasound (US) has revolutionized many medical specialties, including the NM field. It is noninvasive, convenient to use, cost-effective, and pain free. In NM disorders, US enables direct visualization of nerves and muscles. Ultrasound can detect involuntary muscle movement, such as fasciculation and fibrillations, which may improve diagnostic certainty in patients with amyotrophic lateral sclerosis (ALS). Doppler blood flow signals can show muscle vascularization, and finding an increased intramuscular blood flow may be useful to assess inflammatory activity, for example, in patients with myositis [4]. Therefore, US might be useful in diagnosis and possibly to monitor disease progression.
Anzeige
Different types of polyneuropathy (PNP) may show different sonomorphological abnormalities. In general, nerve enlargement is most often seen in demyelinating neuropathies, both inherited and acquired [5]. Chronic axonal polyneuropathies (CAP) show subtle changes in peripheral nerve area measurements on US imaging of the nerves [6]. Axonal loss also leads to secondary structural changes in muscle tissues, manifest on US by loss of muscle thickness and increased echointensity [6‐8]. Consequently, muscle US might serve as a more sensitive indicator for CAP than nerve US imaging. Reference values for US of peripheral nerves [3] and muscle thickness [9] have been established. Possible differences in the pattern of sonographic muscle involvement between acquired CAP, chronic inflammatory demyelinating polyneuropathy (CIDP), and other neuromuscular (NM) disorders are unknown. Furthermore, there are dependent variables that influence muscle thickness such as age, body mass index (BMI), and relaxed/contracted muscles [10]. We aimed to assess whether muscle US showed differences in patients with CAP, CIDP, and other NM diseases compared to controls and to each other.
Methods
Subjects
We performed a cross-sectional study from September 2021 to June 2022, and included consecutive patients attending the Prosserman Family Neuromuscular Clinic of the Toronto General Hospital referred for evaluation of possible NM diseases, including CIDP, CAP, and other conditions. Data from a cohort of normal subjects reported previously [9] were included in the current study, and additional healthy volunteers were recruited from the clinic and hospital staff, and from family members of patients. Healthy subjects who were 18 years old or more, ambulatory, and without any NM disorder were included. Subjects with any neurological disorders, presence of diabetes mellitus (DM) or any medications for other medical disorders were excluded. Inclusion criteria for patients with PNP and other NM diseases included a diagnosis of PNP or other NM disease in symptomatic patients who had confirmation by electrophysiological findings or special laboratory tests to screen for specific etiologies. All subjects provided written informed consent, and the study was approved by the Research Ethics Board of the University Health Network. The authors obtained permission from the developers to use the and Overall Neuropathy Limitation Scale (ONLS) [11] and Rasch-built Overall Disability Score (RODS) [12, 13] scales. The author developed the mTCNS scale and gives permission for its use. The study was conducted in accordance with the Declaration of Helsinki ethical principles regarding clinical research in human subjects.
Clinical Evaluation
The clinical evaluation of patients included a detailed medical history and physical examination, assessment of impairment and disability scales, including the ONLS, RODS, and modified Toronto Clinical Neuropathy Score (mTCNS) [14]. The ONLS is the sum of an arm disability scale score (range 0–5) and a leg disability scale score (range 0–7). The RODS is a structured questionnaire given to patients and contains 24 items graded from easy to difficult to perform, assessing activity limitations and participation restrictions ranging from 0 (maximum limitation) to 48 (normal) [11, 15]. The mTNCS is a scale composed of symptoms and signs of PNP, rated from 0 (normal) to 33 (maximum) [14]. These scales are part of standard practice in the clinic. The Medical Research Centre (MRC) sum score [16] was calculated from the neurological examination findings.
Routine Ancillary Test
Electrophysiological evaluation was performed for diagnosis in all patients and at follow-up visits, if required. The standard laboratory nerve conduction studies included motor and sensory nerve studies from upper and lower limbs: median motor and sensory, ulnar sensory, peroneal motor, tibial motor, and sural and superficial peroneal nerves, supplemented by other nerve conduction studies as required. Our laboratory protocols for CAP, CIDP, radiculopathy, and myopathy were followed as indicated by the patient presentation. Laboratory testing was selective based on the case and as judged by a NM expert (V.B.).
Anzeige
Muscle Ultrasound Protocol
Quantitative muscle thickness measurements using a high-resolution ultrasound machine (LOGIQ S7 Expert; General Electric, Toronto, Canada) and a transducer with a frequency range 5–15 Hz (ML6-15) were performed by a physician experienced in NM imaging. The US examination was performed on the same visit as the clinical evaluation and electrodiagnostic tests. The ultrasonographer was blinded to the details of the clinical history and findings, although the presence of gross muscle atrophy and weakness was apparent in some patients during muscle ultrasonography. Muscle thickness was determined using the US distance measurement function, on both cross-sectional and longitudinal images using the Toronto protocol, and is described elsewhere [9]. Eight muscles were studied bilaterally: biceps, abductor pollicis brevis (APB), abductor digiti minimi, first dorsal interosseous, quadriceps, tibialis anterior, extensor digitorum brevis, and abductor hallucis brevis.
Statistical Analysis
Statistical analyses were performed using SPSS v.23.0 (IBM, Armonk, NY, USA). Normally distributed data were expressed as means ± standard deviations, and the ANOVA test was used for comparisons of groups. Kruskal–Wallis tests and nonparametric pairwise comparisons were used for non-normally distributed data. Ordinal data were expressed as ratios or percent and compared using the chi-square test. Multivariable linear regression analyses were used to compare means of muscle thickness in the different groups. The models were stratified by sex, a separate model was fit using each muscle thickness parameter as the dependent outcome, and age and BMI were included as covariates. P < 0.05 was considered statistically significant for all statistical tests, and the Tukey–Kramer method was used to adjust for multiple pairwise group comparisons in the regression analyses.
Results
We included 160 subjects, 65 healthy controls, and 95 patients with different NM disorders: 31 with CIDP 34 with CAP, and 30 with other NM diseases. Patients with other NM diseases were: ten with myopathy, twelve with myasthenia gravis (MG), two with radiculopathy, two with cramps, one with restless leg syndrome (RLS), two with monoclonal gammopathy of undetermined significance, and one with carpal tunnel syndrome.
Table 1 presents a comparison of demographic information between controls and the different groups. There were more females subjects in the control group and this group was younger compared with patient groups. In the group with CIDP, there were more males. The RODS scale showed greater disability in CIDP than PNP.
Table 1
Demographic variables for CIDP, neuropathy, other NMD, and controls
Variables
CIDP, neuropathy and other NM disease (n = 95)
CIDP (n = 31)
Neuropathy (n = 34)
Other NM disease (n = 30)
Control (n = 65)
p value for trend
Age, y
58.3 ± 16.9
62.67 ± 13.42
60.5 ± 14.52
51.3 ± 20.56
47.09 ± 16
< 0.001
Males, n (%)
60 (63.2%)
26 (83%)
18 (52.9%)
16 (53.3%)
24 (36.9%)
< 0.001
Females, n (%)
35 (36.8%)
5 (16%)
16 (47.1%)
14 (46.7%)
41 (63.1%)
DM, n (%)
25 (26.3%)
12 (38.7%)
8 (23.5%)
5 (16.7%)
3 (4.6%)
< 0.001
BMI, kg/m2
27.3 ± 5.73
26.43 ± 5.18
28.65 ± 6.25
26.65 ± 5.02
25.6 ± 5.07
0.039
MRC_SUM
58.07 ± 4.32
57.03 ± 4.47
59.7 ± .871
57.3 ± 5.83
0.007
Disability scales
RODS
32.1 ± 9.83
38.37 ± 8.91
0.009
mTCNS
15.96 ± 8.1
15.23 ± 7.84
0.732
ONLS
3.65 ± 1.54
2.54 ± 1.5
0.132
DM diabetes; BMI body mass index; MRC_SUM Medical Research Council sum score; RODS Rasch-built Overall Disability Score; ONLS Overall Neuropathy Limitations Scale; mTCNS modified Toronto Clinical Neuropathy Score; CIDP chronic inflammatory demyelinating neuropathy; NM neuromuscular
Both relaxed and contracted muscle US thickness was lower in all patient groups than in the healthy controls (Figs. 1), (Supplemental Table 2a, b). Univariate analysis suggested that muscle thickness in contracted muscles was lower in proximal and distal muscles in CIDP compared to CAP patients who had normal contracted muscle thickness in proximal groups and reduced thickness in distal muscles. However, multivariable regression analyses, including age and BMI as covariates, eliminated these differences between CIDP and CAP. Most differences between patient groups and healthy controls remained after correction for age and BMI, mainly in distal muscles, and in the quadriceps muscles in males (see adjusted pairwise p values shown in Supplementary Table 1a, b).
Fig. 1
Thickness, sex and the four groups, chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy, other neuromuscular (NM) and healthy control group. The closed circles represent each observation, the open represents the mean, and the whiskers represent 1.5 times the interquartile range. (A,B) For males, there are differences across the groups for contracted Abductor Pollices Brevis (APB) and Quadriceps (quad) muscles. (A,B,C,D) For females, there are differences across groups for contracted APB, Tibialis Anterior, Biceps and quad muscles.
×
Discussion
Our results show that patients with CIDP, CAP, and a variety of NM diseases have significantly lower muscle thickness on US, mainly in distal muscles. They also show that there are no statistically significant differences between patient groups, suggesting that the presence and distribution of muscle fiber loss is not specific for any of the patient groups. The latter findings are in contrast to a previous study which showed that several patterns of change in muscle US images can help distinguish between NM disorders [17]. We used a standardized and comprehensive protocol including proximal and distal muscles in the upper and lower limbs in patients with a wide spectrum of NM disorders [17, 18], and the results showed that age and BMI had the most consistent effects on muscle thickness, in agreement with previous studies [19, 20]. The loss of muscle thickness in PNP, including axonal and demyelinating forms of PNP, is most likely the result of nerve fiber degeneration leading to muscle fiber atrophy, although disuse atrophy may also contribute to muscle thickness loss [21]. These findings are in line with published results showing loss of muscle mass in NM disorders [22]. Axonal and muscle fiber loss leads to structural changes in muscle tissues, manifested on US by loss of muscle thickness and increased echointensity [19, 23]. These findings are in line with published results showing loss of muscle mass in NM disorders [22].
After performing post hoc analysis, we found that muscle US does not distinguish between the “other NM disorders”, CIDP, and CAP. This result is intriguing for the “other NM disorders”, as this group included patients with a wide spectrum of disorders, and many did not have clinical weakness nor were they expected to show reduction in muscle thickness (for example, relaxed US thickness in MG patients, or reduced values in those with RLS). Also, despite the greater disability scores in those with CIDP, muscle US thickness could not distinguish this group from those with CAP, after correction for age and BMI, indicating limited sensitivity of muscle US thickness measurements. Nonetheless, muscle US measurements showed an ability to distinguish between healthy subjects and patients with NM diagnoses after corrections for age and BMI.
Our study has several limitations. First, the sample size was small. There were more females in the control group and this group was younger and BMI was slightly lower than the patient groups. However, we corrected these differences by using multivariable analysis. Second, in this study, muscle echointensity was not investigated and this assessment might increase the sensitivity of muscle ultrasound [24]. However, muscle echointensity is highly dependent on machine type and setting, and therefore has limited generalizability, in contrast to muscle thickness that is expected to be similar across different US devices, and therefore of more widespread clinical utility. Also, more distal than proximal muscles were sampled, so that the existing healthy control subjects could be included, and this biases the results towards distally predominant disorders, and reduces the sensitivity for strictly proximal disorders. We did not use relevant disease controls, which may be addressed in future studies. The patients had heterogeneous characteristics which might have influenced the results. We did not collect data on treatment status and duration of disease, and therefore we cannot comment on whether these may be helpful in interpreting muscle US findings.
Anzeige
In conclusion, muscle thickness US is useful for differentiating NM disorders from healthy controls after corrections for age and BMI, but does not appear to be specific for different NM diseases, a limitation of this diagnostic technique. Future collection of treatment status and disease duration may help to interpret muscle US findings. Additional studies expanding the number and distribution of the muscles tested may enable differentiation of NM disorders.
Acknowledgements
The authors wish to acknowledge the patients, family accompanied patients and staff at our clinical sites who participated in this study for their efforts. The Authors also thank the participants of the study.
Funding
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Medical Writing and Editorial Assistance
The authors declare there is no medical writing, editorial or other assistance.
Anzeige
Author Contributions
Sara Alnajjar manuscript writing, analysis and interpretation of data, critical review. Davood Fathihelabad collecting data and review. Leif Lovblom statistical analysis conducted. Alon Abraham, study concept and design and critical review. Lubna Daniyal Performing ultrasound examination. Vera Bril, study concept and design, analysis and interpretation of data, critical revision of manuscript for intellectual content.
Disclosures
Sara A Alnajjar, Davood Fathihelabad, Leif Erik Lovblom, Alon Abraham, Lubna Daniyal and Vera Bril have no conflicts of interest to declare.
Compliance with Ethics Guidelines
All subjects provided written informed consent and the study was approved by the Research Ethics Board of the University Health Network. The authors obtained permission to use the RODS and ONLS scales. The study was conducted in accordance with the declaration of Helsinki ethical principles regarding clinical research in human subjects. The author developed the mTCNS scale and gives permission for its use.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Anzeige
Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Eine ältere Frau trinkt regelmäßig Sennesblättertee gegen ihre Verstopfung. Der scheint plötzlich gut zu wirken. Auf Durchfall und Erbrechen folgt allerdings eine Hyponatriämie. Nach deren Korrektur kommt es plötzlich zu progredienten Kognitions- und Verhaltensstörungen.
Mit einem Neurotrophin-Rezeptor-Modulator lässt sich möglicherweise eine bestehende Alzheimerdemenz etwas abschwächen: Erste Phase-2-Daten deuten auf einen verbesserten Synapsenschutz.
Ein hohes soziales Niveau ist mit die beste Versicherung gegen eine Demenz. Noch geringer ist das Demenzrisiko für Menschen, die sozial aufsteigen: Sie gewinnen fast zwei demenzfreie Lebensjahre. Umgekehrt steigt die Demenzgefahr beim sozialen Abstieg.
Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.
Update Neurologie
Bestellen Sie unseren Fach-Newsletterund bleiben Sie gut informiert.
