Abstract
Background and purpose
Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients.
Methods
Between January 2019 and May 2022, 102 consecutive treatment‐naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow‐up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment‐responsive LMNS (TR‐LMNS).
Results
In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR‐LMNS patients. Six TR‐LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.
Conclusion
Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.
Keywords: amyotrophic lateral sclerosis, diagnosis, inflammatory motor neuropathy, lower motor neuron syndrome, neuromuscular ultrasound
INTRODUCTION
Lower motor neuron (LMN) syndrome comprises a broad spectrum of neurological disorders [1]. Distinguishing inflammatory motor neuropathies (IMNs), such as multifocal motor neuropathy (MMN) and pure motor chronic inflammatory demyelinating polyneuropathy (CIDP), from fatal motor neuron diseases is vital because effective immune therapies are available [1].
Demyelinating features in extensive motor nerve conduction studies (NCSs) are mandatory for fulfilling the diagnostic criteria of CIDP [2, 3]. The presence of conduction block (CB), which was initially recognized as a feature of focal demyelination but was hypothesized to be evidence of functional disturbance at the node of Ranvier in recent literature [4, 5, 6], was the hallmark of MMN [7, 8]. However, CB might not be detectable in some patients, probably because CBs are activity‐dependent [9] or because the locations are in the proximal or distal segments [7, 10]. In addition, other surrogates of demyelination (such as conduction velocity slowing and temporal dispersion) may also be undetectable if they are located in proximal segments. Therefore, a diagnosis of IMN should not be excluded when there is no evidence of demyelination in NCSs. Additional diagnostic modalities can help differentiate LMN syndromes, for example nerve ultrasound (US) abnormalities in chronic inflammatory neuropathies [11, 12, 13] and the distribution of fasciculations on muscle US in amyotrophic lateral sclerosis (ALS) [14, 15]. Only a few cases of IMN without electrodiagnostic evidence of demyelination have been reported, in part due to the rarity of motor CIDP and MMN in general [10, 16, 17, 18, 19, 20, 21].
In this study, the aim was to assess the diagnostic performance of nerve and muscle US amongst consecutive lower motor neuron syndrome (LMNS) patients, and to evaluate whether these methods could provide added value for the identification of IMN compared to routine NCSs.
METHODS
Study design and patients
This single‐center, examiner‐blinded, prospective cohort study was performed between January 2019 and May 2022 at Peking Union Medical College Hospital. Consecutive treatment‐naïve LMNS patients with a clinical suspicion of MMN, pure motor CIDP or ALS with initial LMN presentation were recruited. The inclusion criteria were as follows: (i) progressive limb weakness and (ii) chronic or subacute onset. The exclusion criteria for this study were (i) age at onset <18 years old; (ii) disease duration ≥10 years; (iii) family history of muscle weakness and atrophy; (iv) presence of clinical upper motor neuron signs (spasticity, increased muscle tone, hyperreflexia and pathological reflexes); (v) clinical involvement of the bulbar region or respiratory function impairment; (iv) sensory abnormalities identified by sensory NCS; or (vii) inability to undergo nerve and muscle US studies.
This study was approved by the ethical committee of Peking Union Medical College Hospital. Written informed consent was obtained from each subject.
Patient demographic, clinical and laboratory data
All patients underwent a standardized face‐to‐face interview at the first consultation. The demographic and basic clinical features, including age, sex, body mass index, site of symptom onset and disease duration, were collected. Questionnaires including the overall neuropathy limitations scale [22] and ALS Functional Rating Scale Revised [23] were used to evaluate functional disability. In addition, the muscle strength of bilateral upper and lower limbs was graded using the Medical Research Council (MRC) scale as previously described [14], and the total MRC sum score was 160.
Routine laboratory investigations were performed to screen for infection, malignancy and systemic autoimmune diseases. Additional tests, including needle electromyography (EMG), spinal magnetic resonance imaging (MRI), brachial plexus MRI, lumbar puncture and genetic testing, were also conducted if clinically warranted.
All patients underwent NCSs according to the standardized protocol as previously described with a Nicolet electromyograph machine (CareFusion, Middleton, WI, USA) [24]. Briefly, motor NCSs were applied to the median, ulnar, fibular and tibial nerves via percutaneous supramaximal nerve stimulation. If neurophysiological examinations indicated that the neurogenic lesions were principally located in the territories of the radial nerve, the bilateral radial nerves were examined. F waves were detected with repetitive supramaximal stimulations at a rate of 1 Hz on the bilateral median and tibial nerves. Orthodromic sensory NCSs were performed on the median, ulnar, medial plantar and superficial fibular nerves. In this study, electrodiagnostic evidence of IMN was defined as temporal dispersion, nerve conduction slowing, prolongation of F‐wave latencies, or CB on motor NCSs according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria [3, 7].
Nerve and muscle US
To look for ultrasonographic evidence of IMN, nerve and muscle US studies were performed on all patients at baseline. The examiner (LZ) was blinded to the clinical and laboratory information. Investigations were performed with an 8–12 MHz linear array transducer (LOGIQ e; General Electric). Patients were indicated to lie in the supine position or in the prone position with their limbs extended and relaxed, depending on the muscle groups or nerves examined, and they were indicated to rest for 2 min after they changed the position. During the whole process, the skin temperature was >32°C.
The whole process of nerve US took approximately 15 min following the protocol described previously [24]. The cross‐sectional areas (CSAs) of the bilateral median nerve, ulnar nerve and cervical 5–7 nerve roots were measured (common sites of nerve compression were excluded, as shown in Table S1). Previously published normal values [25] were used as the reference values for the following reasons: (i) this study consecutively recruited LMNS patients with combined clinical diagnoses, and it was considered inappropriate to use specific cutoff values for distinguishing specific diseases; (ii) the nerve CSAs of ALS were reported to be slightly smaller [26] or not significantly different from those of healthy subjects [27], whilst nerve enlargements were reported in MMN or CIDP patients [11, 24, 28], which might guarantee the effectiveness of normal values as a reference for distinguishing IMN and ALS.
The muscle US studies were conducted according to our previously described procedure [14] with some modifications and took 10–30 min. In clinical practice, it was noticed that sometimes fasciculations were more likely to be present in the junction area of several small muscles (as shown in Videos S1 and S2). Hence, the muscle groups were extensively examined rather than the separate muscles to increase the fasciculation detection rate. At most, 18 muscle groups were assessed for each patient (Table S2). First, the transducer was transversely placed at the middle of the muscle group for 10 s. If no high intensity fasciculations were observed, the transducer was held in the same position for another 10 s. Then, if no high intensity fasciculations were observed, the transducer was moved medially or laterally for 2 cm in the same muscle group. As described in our previous work, high intensity fasciculations were defined as fasciculations present at three or more sites in the area tested in 10 s.
For the purpose of this study, US evidence of IMN was categorized as follows: (i) nerve enlargement was detected at ≥1 of the predetermined sites (nerve US +); or (ii) fasciculations of high intensity were absent in any of the 18 muscle groups (muscle US +).
Treatment, follow‐up and diagnosis
Treatment strategies were based on the treating neurologist's index of suspicion and the willingness of patients. Generally, patients were treated when they met any of the following criteria: (i) presence of electrodiagnostic evidence; (ii) ultrasonographic evidence was present; (iii) presence of other features indicating IMN (such as early onset, slower progression, positive serum anti‐GM1 antibodies and high cerebrospinal fluid protein levels); or (iv) anyone who wanted to try intravenous immunoglobulin (IVIg) even if no other laboratory, electrophysiological or imaging findings supported the diagnosis of IMN. Patients were not treated if they refused treatment or if other diagnoses were highly suspected.
Each patient was followed up for at least 12 months. The final diagnoses were re‐examined by two experienced physicians (JWN and MSL) in May 2023, and disagreements were resolved by consensus. A diagnosis of treatment‐responsive LMNS (TR‐LMNS) was made when patients met the following criteria: (i) electrodiagnostic studies detected no features of demyelination; and (ii) convincing improvements were observed during a follow‐up period of at least 12 months. A clinical improvement was defined as follows: (i) overall neuropathy limitations scale increase ≥1 point; (ii) ALS Functional Rating Scale Revised increase ≥1 point; or (iii) MRC sum score increase ≥4 points. Patients fulfilling the EFNS/PNS electrodiagnostic criteria were diagnosed with MMN or CIDP [3, 7]. Patients were diagnosed with ALS according to the Gold Coast criteria [29].
Statistical analysis
The software IBM SPSS Statistics, version 22, was used for statistical analysis. Data with a normal distribution were summarized as the mean (SD), and those with a non‐normal distribution were summarized as the median (min–max). Categorical variables were summarized as n (%). The t test, the Mann–Whitney U test and Fisher's exact test were used to compare the clinical features between groups depending on the distribution of the variables. All tests were two tailed, and the significance level was set to 0.05. The sensitivity, specificity, positive predictive value and negative predictive value were calculated from 2 × 2 tables.
RESULTS
Baseline clinical characteristics
Between January 2019 and May 2022, 884 patients complained of muscle weakness and visited our ALS Center at Peking Union Medical College Hospital. After fulfilling the selection criteria, a total of 102 LMNS patients were enrolled—76 men and 26 women. The baseline demographic and clinical features of these 102 patients are summarized in Table 1. Amongst the 102 LMNS patients, 93 patients exhibited no features of demyelination on NCS.
TABLE 1.
The baseline clinical characteristics of 102 LMNS patients with a clinical suspicion of MMN, pure motor CIDP or ALS with initial LMN presentation.
| Total (n = 102) | LMNS without demyelination on NCS (n = 93) | |
|---|---|---|
| Onset age (years), mean (SD) | 51.3 (11.6) | 52.1 (11.3) |
| Male, n (%) | 76 (74.5) | 70 (75.3) |
| BMI, mean (SD) | 24.4 (3.5) | 24.2 (3.6) |
| Disease duration (months), median (min–max) | 12 (2–95) | 12 (2–88) |
| Onset site, n (%) | ||
| U‐PUL | 13 (12.7) | 13 (14.0) |
| U‐DUL | 49 (48.0) | 45 (48.4) |
| U‐PLL | 10 (9.8) | 10 (10.8) |
| U‐DLL | 16 (15.7) | 15 (16.1) |
| B‐PUL | 1 (1.0) | 1 (1.1) |
| B‐DUL | 3 (2.9) | 2 (2.2) |
| B‐PLL | 7 (6.9) | 7 (7.5) |
| B‐DLL | 2 (2.0) | 0 (0) |
| Four limbs | 1 (1.0) | 0 (0) |
|
MRC sum score, median (min–max) |
141.0 (92.0–157.5) | 141.0 (97.0–157.5) |
| ONLS, median (min–max) | 3 (1–10) | 3 (1–9) |
| ALSFRS‐R, median (min–max) | 43 (29–47) | 43 (32–47) |
Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; B, bilateral; BMI, body mass index; CIDP, chronic inflammatory demyelinating polyneuropathy; D, distal; LL, lower limb; LMN, lower motor neuron; LMNS, lower motor neuron syndrome; MMN, multifocal motor neuropathy; MRC, Medical Research Council; NCS, nerve conduction study; ONLS, overall neuropathy limitations scale; P, proximal; SD, standard deviation; U, unilateral; UL, upper limb.
Follow‐up and final diagnoses
The final diagnoses are shown in the study flowchart (Figure 1) and Table 2. In addition, the proportions of patients with US findings suggestive of IMN in the different groups are listed in Table S6. In total, 39 patients were treated, including 30 patients without demyelination on NCSs (the reasons for treatment are listed in Table S3) and nine patients who fulfilled the electrodiagnostic criteria for MMN/CIDP. The other 63 patients were not treated; five patients had ultrasonographic evidence of IMN (details are exhibited in Table S4, and Figures S1 and S2).
FIGURE 1.
Study flowchart. In the present study, the US characteristics listed below are categorized as US evidence of TR‐LMNS: (1) nerve enlargements detected at one or more of the predetermined sites (nerve US +); (2) fasciculations of high intensity not observed in any of the 18 muscle groups (muscle US +).
TABLE 2.
The clinical characteristics of LMNS patients with different final diagnoses.
| MMN/CIDP (n = 9) | TR‐LMNS (n = 7) | Others (n = 86) | p value | |
|---|---|---|---|---|
|
Onset age (years), mean (SD) |
43.0 (12.6) | 49.3 (10.4) | 52.3 (11.4) |
0.304 a 0.493 b |
| Male, n (%) | 6 (66.7) | 7 (100) | 63 (73.3) |
0.213 a 0.187 b |
|
BMI, mean (SD) |
25.7 (2.0) | 24.8 (1.6) | 24.2 (3.8) |
0.332 a 0.671 b |
|
Disease duration (months), median (min–max) |
29 (3–96) | 14 (3–60) | 12 (2–88) |
0.606 a 0.971 b |
| Onset site, n (%) | ||||
| U‐PUL | 0 | 0 | 13 (15.1) | 0.736 a |
| U‐DUL | 4 (44.4) | 5 (71.4) | 40 (46.5) | 0.860 b |
| U‐PLL | 0 | 1 (14.3) | 9 (10.5) | |
| U‐DLL | 1 (11.1) | 1 (14.3) | 14 (16.3) | |
| B‐PUL | 0 | 0 | 1 (1.2) | |
| B‐DUL | 1 (11.1) | 0 | 2 (2.3) | |
| B‐PLL | 0 | 0 | 7 (8.1) | |
| B‐DLL | 2 (22.2) | 0 | 0 | |
| Four limbs | 1 (11.1) | 0 | 0 | |
| MRC sum score, median (min–max) | 141.0 (92.0–149.0) | 140.0 (127.0–154.0) | 141.5 (97.0–157.5) |
0.859 a 0.650 b |
| ONLS, median (min–max) | 3 (2–10) | 2 (2–5) | 3 (1–9) |
0.347 a 0.650 b |
| ALSFRS‐R, median (min–max) | 42 (29–45) | 44 (42–46) | 43 (32–47) |
0.306 a 0.321 b |
Note: “Others” includes 83 ALS patients, one KD patient, one HD patient, and one undiagnosed patient.
Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; B, bilateral; BMI, body mass index; CIDP, chronic inflammatory demyelinating polyneuropathy; D, distal; HD, Hirayama disease; KD, Kennedy disease; LL, lower limb; LMNS, lower motor neuron syndrome; MMN, multifocal motor neuropathy; MRC, Medical Research Council; ONLS, overall neuropathy limitations scale; P, proximal; SD, standard deviation; TR‐LMNS, treatment‐responsive lower motor neuron syndrome; U, unilateral; UL, upper limb.
TR‐LMNS versus MMN/CIDP.
TR‐LMNS versus Others.
Eventually, 16 patients responded to immune therapies, including nine MMN/CIDP patients and seven TR‐LMNS patients without electrodiagnostic features of demyelination. In one female patient (muscle US +), symptoms seemed to stop exacerbating during the 1‐year follow‐up period after IVIg administration. Since this patient did not meet the predefined criteria for clinical improvement, she was not categorized as having TR‐LMNS, and continued follow‐up was warranted to establish the final diagnosis. Amongst the other 22 treated patients, the condition steadily deteriorated, and they were diagnosed with ALS. For the 63 untreated patients, the final diagnoses were established during the follow‐up periods. Sixty‐one patients were diagnosed with ALS according to the Gold Coast criteria, one patient was genetically confirmed to have Kennedy disease, and one patient was diagnosed with Hirayama disease according to clinical features and typical MRI findings.
Table 2 shows the comparisons between patients with TR‐LMNS, MMN/CIDP and other diagnoses. All the TR‐LMNS patients were male, whilst the groups did not significantly differ in gender, or in the onset age, body mass index, disease duration, symptom onset site or baseline motor function.
The detailed clinical data of the seven TR‐LMNS patients are exhibited in Table 3. The majority of these TR‐LMNS patients (six patients) exhibited US evidence of IMN. All patients received immunotherapies and experienced convincing recovery to different extents. Six patients received at least one course of IVIg, five of whom exhibited convincing improvements. Only one patient (patient 1) who did not experience clinical improvement after IVIg treatment received oral cyclophosphamide (CTX) for 3 months, after which his symptoms gradually improved. During the follow‐up period, five TR‐LMNS patients (patients 1, 2, 3, 5 and 6) underwent repeated NCSs when their symptoms improved at least 3 months later, whilst CB and nerve conduction slowing were detected in only one patient (patient 1).
TABLE 3.
The detailed clinical features and treatments of seven TR‐LMNS cases without electrodiagnostic evidence of demyelination.
| Patient (sex/onset age) | Disease duration (months) | Disease progression pattern | Nerve US | Muscle US | Serum anti‐GM1 antibodies | CSF WBC (/μL)/protein (g/L) | Plexus MRI | Treatments (effectiveness) | MRC B, LE | ONLS B, LE | ALSFRS‐R B, LE | Follow‐up (months) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IVIg | CTX | ||||||||||||
| 1 (M/43) | 5 | LDLL → RDLL → LDUL | Negative | Positive | Negative | 4/0.35 | Negative | Yes (−) | Yes (+) | 127, 149 | 5, 2 | 42, 45 | 22 |
| 2 (M/43) | 17 | RDUL → LDUL → both DLL | Positive | Positive | Negative | 4/0.45 | Negative | Yes (+) | No | 140, 151 | 4, 2 | 42, 46 | 19 |
| 3 (M/67) | 3 | RDUL →RPUL | Negative | Positive | Negative | 0/0.37 | Negative | Yes (+) | No | 138, 155 | 2, 1 | 44, 46 | 17 |
| 4 (M/46) | 13 | LPLL → RPLL → both DLL | Negative | Positive | Negative | 2/0.32 | Negative | No | Yes (+) | 136, 148 | 3, 2 | 42, 45 | 16 |
| 5 (M/36) | 8 | LDUL → LDLL | Negative | Positive | Negative | 2/0.47 | NP | Yes (+) | No | 154, 160 | 2, 0 | 46, 48 | 36 |
| 6 (M/54) | 60 | LDUL → RDUL | Positive | Positive | Negative | NP | Negative | Yes (+) | No | 142.5, 147.5 | 2, 2 | 45, 46 | 13 |
| 7 (M/56) | 18 | LDUL → LPUL | Negative | Negative | Negative | NP | Negative | Yes (+) | No | 152, 158 | 2, 2 | 45, 47 | 12 |
Abbreviations: −, noneffective; +, effective; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; B, at baseline; CTX, cyclophosphamide; CSF, cerebrospinal fluid; D, distal; IVIg, intravenous immunoglobulin; L, left; LE, at last examination; LL, lower limb; MRC, Medical Research Council; NP, not performed; ONLS, overall neuropathy limitations scale; P, proximal; R, right; TR‐LMNS, treatment‐responsive lower motor neuron syndrome; UL, upper limb; US, ultrasound; WBC, white blood cell.
Diagnostic accuracies of neuromuscular US and NCSs
The diagnostic accuracies of the different modalities are summarized in Table 4. In brief, the sensitivity and specificity of NCSs for predicting a treatment response were 56.3% and 100%, respectively. The sensitivity and specificity of nerve US alone were 43.80% and 90.70%, respectively. The sensitivity and specificity of muscle US were 68.80% and 97.70%, respectively. When the three diagnostic modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.
TABLE 4.
Diagnostic accuracies of neuromuscular ultrasound and NCSs for identifying IMN from LMNSs.
| NCS | Nerve US | Muscle US | Nerve US or muscle US | Nerve US or muscle US or NCS | |
|---|---|---|---|---|---|
| Test positive/total positive sensitivity, n (%) | 9/16 (56.3) | 7/16 (43.8) | 11/16 (68.8) | 13/16 (81.3) | 15/16 (93.8) |
| Test negative/total negative specificity, n (%) | 86/86 (100) | 78/86 (90.7) | 84/86 (97.7) | 76/86 (88.4) | 76/86 (88.4) |
| NPV, % | 100 | 46.7 | 84.6 | 56.5 | 60 |
| PPV, % | 92.5 | 89.7 | 94.4 | 96.2 | 98.7 |
Abbreviations: IMN, inflammatory motor neuropathy; LMNS, lower motor neuron syndrome; NCS, nerve conduction study; NPV, negative predictive value; PPV, positive predictive value; US, ultrasound.
DISCUSSION
Herein, 102 consecutive LMNS patients who presented with progressive limb weakness were prospectively enrolled to investigate the added value of nerve and muscle US for improving the detection of IMNs, making this cohort study the largest single‐center diagnostic study recruiting series of such patients to date. It was revealed that nerve enlargement and the absence of high intensity fasciculations, as assessed by nerve and muscle US studies, were useful predictive indicators of treatable motor neuropathies.
Identification of treatment‐responsive patients with pure LMN lesions from mimics, such as ALS with initial LMN presentation, is of paramount importance but often difficult. Although electrodiagnostic studies are recognized as complementary techniques [3, 7], strict application of the electrodiagnostic criteria for MMN/CIDP can lead to misdiagnosis and delay the treatment of a few treatable LMNS patients without demyelinating features [10, 16, 17, 18, 19, 20, 21, 30, 31, 32, 33]. In this study, a total of 16 patients (15.7%) improved after treatment. Seven treatment‐responders presented without electrodiagnostic demyelination features and accounted for 7.5% of the 93 LMNS patients without demyelination evidence, which was consistent with the findings of Simon and his colleagues (the rate of treatment response was 9.7% in LMNS patients, and they recommended not uniformly using IVIg in this set of patients) [19]. In contrast, earlier studies reported a higher response rate [10, 16, 32, 33]. This discrepancy might be partly attributed to the selection of patients with markedly longer disease durations (mean disease duration ≥4.5 years) in earlier studies, which naturally excluded most ALS patients with initial LMN lesions, and partly attributed to the fact that some researchers recruited LMNS patients without CB (patients with other demyelination features were not excluded). The seven TR‐LMNS patients in our study presented with asymmetric limb weakness (the clinical phenotype of MMN) and were more likely to have MMN without detectable CB. Furthermore, in this study, the baseline demographic and clinical characteristics of the seven TR‐LMNS patients were similar to those of patients with other diagnoses (mainly ALS), which complicated the differential diagnosis.
The usefulness of nerve US for providing additional information for the diagnosis of chronic inflammatory neuropathy has been proven by an increasing number of studies [11, 18, 27, 34]. To test the value of nerve US for identifying IMN in LMNS patients, nerve US studies were conducted in all 102 patients at baseline. In previous studies, nerve morphology was detected at only two sites on the median or ulnar nerve. In contrast, each nerve at seven predetermined sites was examined to increase the detection rate of nerve enlargement because nerve enlargements in MMN patients were distributed along the nerves in a patchy form as reported previously [28, 35]. In this study, slight nerve enlargements at one or more sites was observed in 15 patients (five with NCS abnormalities, 10 without NCS abnormalities), and only seven patients were treatment responders. Surprisingly, the diagnostic performance of nerve US alone was poorer than that of NCSs, but the former identified two additional patients who responded to immunotherapies without NCS evidence of demyelination. This phenomenon might be partly explained by the fact that motor nerve CB was not always consistent with increased CSA [28, 35], and either nerve enlargements or CB could be located in not detectable areas, such as in the extremely proximal or distal segments. Moreover, because motor axons account for an average of 6% of the total axons constituting the median nerve, ulnar nerve and nerve roots [36], motor axon loss or slight injuries involving demyelination and remyelination might have no significant effect on nerve CSAs, which might also partially explain the phenomenon that some treatment responders (three MMN, one CIDP and five TR‐LMNS) exhibited no nerve enlargement. In this study, eight ALS patients (8/83, 9.6%) exhibited slightly enlarged nerves sporadically compared to normal values, and the slight enlargement of the nerve segments was attributed to individual differences.
Fasciculations are considered to be an important and the earliest sign of ALS patients [37, 38] and can be effectively detected by muscle US compared to EMG [39, 40, 41], whilst in patients with ALS mimics, such as CIDP and MMN, fasciculations tend to be related to the process of axonal regeneration and re‐innervation and might occur in the later chronic phase of the disease [38]. Moreover, although Vázquez‐Costa et al. [42] revealed that fasciculation intensities were associated with muscle weakness and atrophy in an inverted U‐shaped pattern, Avidan et al. [43] reported that fasciculations in at least one muscle were present in almost all ALS patients (87/90, 97.8%). Hence, it was speculated that, in the relatively early disease stages, patients without high intensity fasciculations were unlikely to have ALS. Fortunately, these results were consistent with our hypothesis that high intensity fasciculations were absent in 13 patients, and none of these patients were diagnosed with ALS by the end of the study (11 treatment‐responders, one Hirayama disease and one undiagnosed). From the other perspective, our work also suggested that if NCSs do not meet the criteria of demyelination and high intensity fasciculations are present, then a diagnosis of ALS is highly likely. In clinical practice, fasciculations might also be detected by clinical observation and EMG detection. However, the detection rate is significantly lower than that of muscle US, as mentioned above, and no specific criteria for measuring fasciculations or defining the “pathological” or “physiological” characteristics has been established (e.g., sporadic fasciculations might also appear in healthy subjects and peripheral neuropathies; if subjects have sporadic fasciculations, it would be improper to consider a diagnosis of ALS), which might limit the use of EMG detection or clinical observation of fasciculations in clinical practice for early diagnosis of ALS. Hence, it is recommended that muscle US studies be performed in LMNS patients in clinical practice to differentiate IMN from other diseases, such as ALS.
In our work, nine MMN patients (including six TR‐LMNS patients) presented without high intensity fasciculations. In contrast, in the study of Tsuji and his colleagues [15], it was found that muscle motion of fasciculations was similar between MMN and ALS patients, and fasciculations were detectable in at least one lower limb muscle in all five MMN patients. This discrepancy might be explained by the following factors. (i) The authors recruited a relatively small number of MMNs. (ii) Patients in our study were treatment‐naïve and had a much shorter disease duration. As mentioned above, in CIDP and MMN, fasciculations might be related to the process of axonal regeneration and re‐innervation and might appear in the later disease course when symptoms are relieved or stable. Similarly, Cappelen‐Smith et al. [44] demonstrated that abnormalities in axonal excitability are not generalized to early MMN. (iii) It is also possible that TR‐LMNS is a different entity, for example “chronic inflammatory axonal polyneuropathy” [45], rather than MMN without CB. To clarify the evolution of excitability and fasciculation patterns in treatable ALS mimics, such as MMN, and to gain insight into TR‐LMNS, further studies with more cases and long‐term follow‐up are necessary, which ultimately might improve the utilization of muscle US in distinguishing LMNSs.
Our study has several limitations. First, no standardized treatment strategies were employed in this study, and treatments were based on the treating neurologist's index of suspicion and the willingness of the patients. Secondly, CTX was used in two TR‐LMNS patients; CTX was not routinely used for patients with pure LMN syndrome and might be toxic. However, CTX was demonstrated to have a beneficial effect on MMN patients [7], and patients had financial difficulty in repeated IVIg infusions (one patient could not afford the first course of IVIg treatment). Another limitation was that the combined use of neuromuscular US and NCS in all suspected LMNS patients might be exhausted. In our practical experience, a great amount of fasciculations could be observed in the upper limbs in most ALS patients, in accordance with previous work [43]. To solve this problem, it was suggested that sonographers start from the upper arms and terminate muscle US studies once fasciculations of high intensity are detected to save time.
In general, the combined use of neuromuscular US (especially muscle US) with NCS might improve the detection of IMN in LMNS patients. It is recommended that NCS be chosen as the primary investigative strategy, and then, for patients without electrodiagnostic evidence of demyelination, nerve and muscle US studies should be conducted.
AUTHOR CONTRIBUTIONS
Lei Zhang: Methodology; conceptualization; writing – original draft; data curation. Yi Li: Data curation; conceptualization. Jingwen Niu: Data curation; conceptualization; supervision. Nan Hu: Data curation. Jianfeng Ding: Data curation. Liying Cui: Conceptualization; supervision; data curation; resources. Mingsheng Liu: Conceptualization; writing – review and editing; data curation; supervision; resources; validation.
CONFLICT OF INTEREST STATEMENT
None of the authors has any conflicts of interest to disclose.
ETHICS STATEMENT
It is confirmed that the journal's position on issues involved in ethical publication have been read and it is affirmed that this report is consistent with those guidelines.
Supporting information
Figure S1
Figure S2
Table S1
Table S2
Table S3
Table S4
Table S5
Table S6
Video S1
Video S2
ACKNOWLEDGEMENTS
This work was supported by National High Level Hospital Clinical Research Funding (2022‐PUMCH‐B‐017), CAMS Innovation Fund for Medical Sciences (CIFMS 2021‐I2M‐1‐003), the Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (grant XDB39040000) and the National Key Research and Development Program of China (2016YFC0905103).
Zhang L, Li Y, Niu J, et al. Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes. Eur J Neurol. 2024;31:e16202. doi: 10.1111/ene.16202
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1. Garg N, Park SB, Vucic S, et al. Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 2017;88:474‐483. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force—second revision. Eur J Neurol. 2021;28:3556‐3583. [DOI] [PubMed] [Google Scholar]
- 3. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. J Peripher Nerv Syst. 2010;15:1‐9. [DOI] [PubMed] [Google Scholar]
- 4. Straver DC, van Asseldonk JT, Notermans NC, Wokke JH, van den Berg LH, Franssen H. Cold paresis in multifocal motor neuropathy. J Neurol. 2011;258:212‐217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Uncini A, Susuki K, Yuki N. Nodo‐paranodopathy: beyond the demyelinating and axonal classification in anti‐ganglioside antibody‐mediated neuropathies. Clin Neurophysiol. 2013;124:1928‐1934. [DOI] [PubMed] [Google Scholar]
- 6. Yeh WZ, Dyck PJ, van den Berg LH, Kiernan MC, Taylor BV. Multifocal motor neuropathy: controversies and priorities. J Neurol Neurosurg Psychiatry. 2020;91:140‐148. [DOI] [PubMed] [Google Scholar]
- 7. PNS JTFotEat . European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. J Peripher Nerv Syst. 2010;15:295‐301. [DOI] [PubMed] [Google Scholar]
- 8. Vlam L, van der Pol WL, Cats EA, et al. Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat Rev Neurol. 2011;8:48‐58. [DOI] [PubMed] [Google Scholar]
- 9. Nodera H, Bostock H, Izumi Y, et al. Activity‐dependent conduction block in multifocal motor neuropathy: magnetic fatigue test. Neurology. 2006;67:280‐287. [DOI] [PubMed] [Google Scholar]
- 10. Delmont E, Azulay JP, Giorgi R, et al. Multifocal motor neuropathy with and without conduction block: a single entity? Neurology. 2006;67:592‐596. [DOI] [PubMed] [Google Scholar]
- 11. Herraets IJT, Goedee HS, Telleman JA, et al. Nerve ultrasound improves detection of treatment‐responsive chronic inflammatory neuropathies. Neurology. 2020;94:e1470‐e1479. [DOI] [PubMed] [Google Scholar]
- 12. Eftimov F, Lucke IM, Querol LA, Rajabally YA, Verhamme C. Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy. Brain. 2020;143:3214‐3224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Lucke IM, Adrichem ME, Wieske L, et al. Intravenous immunoglobulins in patients with clinically suspected chronic immune‐mediated neuropathy. J Neurol Sci. 2019;397:141‐145. [DOI] [PubMed] [Google Scholar]
- 14. Liu J, Li Y, Niu J, et al. Fasciculation differences between ALS and non‐ALS patients: an ultrasound study. BMC Neurol. 2021;21:441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Tsuji Y, Noto YI, Kitaoji T, Kojima Y, Mizuno T. Difference in distribution of fasciculations between multifocal motor neuropathy and amyotrophic lateral sclerosis. Clin Neurophysiol. 2020;131:2804‐2808. [DOI] [PubMed] [Google Scholar]
- 16. Katz JS, Barohn RJ, Kojan S, et al. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology. 2002;58:615‐620. [DOI] [PubMed] [Google Scholar]
- 17. Briani C, Cacciavillani M, Lucchetta M, Cecchin D, Gasparotti R. MR neurography findings in axonal multifocal motor neuropathy. J Neurol. 2013;260:2420‐2422. [DOI] [PubMed] [Google Scholar]
- 18. Goedee HS, Herraets IJT, Visser LH, et al. Nerve ultrasound can identify treatment‐responsive chronic neuropathies without electrodiagnostic features of demyelination. Muscle Nerve. 2019;60:415‐419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Simon NG, Ayer G, Lomen‐Hoerth C. Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block? Neurology. 2013;81:2116‐2120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Doneddu PE, Cocito D, Manganelli F, et al. Atypical CIDP: diagnostic criteria, progression and treatment response. Data from the Italian CIDP database. J Neurol Neurosurg Psychiatry. 2019;90:125‐132. [DOI] [PubMed] [Google Scholar]
- 21. Doneddu PE, Akyil H, Manganelli F, et al. Unclassified clinical presentations of chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry. 2023;94:614‐621. [DOI] [PubMed] [Google Scholar]
- 22. Graham RC, Hughes RA. A modified peripheral neuropathy scale: the overall neuropathy limitations scale. J Neurol Neurosurg Psychiatry. 2006;77:973‐976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS‐R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (phase III). J Neurol Sci. 1999;169:13‐21. [DOI] [PubMed] [Google Scholar]
- 24. Niu J, Li Y, Liu T, et al. Serial nerve ultrasound and motor nerve conduction studies in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2019;60:254‐262. [DOI] [PubMed] [Google Scholar]
- 25. Niu J, Li Y, Zhang L, Ding Q, Cui L, Liu M. Cross‐sectional area reference values for sonography of nerves in the upper extremities. Muscle Nerve. 2020;61:338‐346. [DOI] [PubMed] [Google Scholar]
- 26. Nodera H, Takamatsu N, Shimatani Y, et al. Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography. Clin Neurophysiol. 2014;125:1906‐1911. [DOI] [PubMed] [Google Scholar]
- 27. Grimm A, Décard BF, Athanasopoulou I, Schweikert K, Sinnreich M, Axer H. Nerve ultrasound for differentiation between amyotrophic lateral sclerosis and multifocal motor neuropathy. J Neurol. 2015;262:870‐880. [DOI] [PubMed] [Google Scholar]
- 28. Rattay TW, Winter N, Décard BF, et al. Nerve ultrasound as follow‐up tool in treated multifocal motor neuropathy. Eur J Neurol. 2017;24:1125‐1134. [DOI] [PubMed] [Google Scholar]
- 29. Shefner JM, Al‐Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for ALS. Clin Neurophysiol. 2020;131:1975‐1978. [DOI] [PubMed] [Google Scholar]
- 30. Pestronk A, Cornblath DR, Ilyas AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol. 1988;24:73‐78. [DOI] [PubMed] [Google Scholar]
- 31. Yuki N, Yanaka C, Sudo M, et al. Lower motor neuron syndrome associated with IgG anti‐GM1 antibodies revisited. J Neuroimmunol. 2014;272:62‐66. [DOI] [PubMed] [Google Scholar]
- 32. Ellis CM, Leary S, Payan J, et al. Use of human intravenous immunoglobulin in lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 1999;67:15‐19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Strigl‐Pill N, König A, Schröder M, et al. Prediction of response to IVIg treatment in patients with lower motor neurone disorders. Eur J Neurol. 2006;13:135‐140. [DOI] [PubMed] [Google Scholar]
- 34. Loewenbrück KF, Liesenberg J, Dittrich M, et al. Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). J Neurol. 2016;263:35‐44. [DOI] [PubMed] [Google Scholar]
- 35. Li Y, Niu J, Liu T, et al. Conduction block and nerve cross‐sectional area in multifocal motor neuropathy. Front Neurol. 2019;10:1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Gesslbauer B, Hruby LA, Roche AD, Farina D, Blumer R, Aszmann OC. Axonal components of nerves innervating the human arm. Ann Neurol. 2017;82:396‐408. [DOI] [PubMed] [Google Scholar]
- 37. de Carvalho M, Swash M. Fasciculation potentials and earliest changes in motor unit physiology in ALS. J Neurol Neurosurg Psychiatry. 2013;84:963‐968. [DOI] [PubMed] [Google Scholar]
- 38. de Carvalho M, Kiernan MC, Swash M. Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance. J Neurol Neurosurg Psychiatry. 2017;88:773‐779. [DOI] [PubMed] [Google Scholar]
- 39. Misawa S, Noto Y, Shibuya K, et al. Ultrasonographic detection of fasciculations markedly increases diagnostic sensitivity of ALS. Neurology. 2011;77:1532‐1537. [DOI] [PubMed] [Google Scholar]
- 40. Hobson‐Webb LD, Simmons Z. Ultrasound in the diagnosis and monitoring of amyotrophic lateral sclerosis: a review. Muscle Nerve. 2019;60:114‐123. [DOI] [PubMed] [Google Scholar]
- 41. Grimm A, Prell T, Décard BF, et al. Muscle ultrasonography as an additional diagnostic tool for the diagnosis of amyotrophic lateral sclerosis. Clin Neurophysiol. 2015;126:820‐827. [DOI] [PubMed] [Google Scholar]
- 42. Vázquez‐Costa JF, Campins‐Romeu M, Martínez‐Payá JJ, et al. New insights into the pathophysiology of fasciculations in amyotrophic lateral sclerosis: an ultrasound study. Clin Neurophysiol. 2018;129:2650‐2657. [DOI] [PubMed] [Google Scholar]
- 43. Avidan R, Fainmesser Y, Drory VE, Bril V, Abraham A. Fasciculation frequency at the biceps brachii and brachialis muscles is associated with amyotrophic lateral sclerosis disease burden and activity. Muscle Nerve. 2021;63:204‐208. [DOI] [PubMed] [Google Scholar]
- 44. Cappelen‐Smith C, Kuwabara S, Lin CS, Burke D. Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy. Muscle Nerve. 2002;26:769‐776. [DOI] [PubMed] [Google Scholar]
- 45. Oh SJ, Lu L, Alsharabati M, Morgan MB, King P. Chronic inflammatory axonal polyneuropathy. J Neurol Neurosurg Psychiatry. 2020;91:1175‐1180. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1
Figure S2
Table S1
Table S2
Table S3
Table S4
Table S5
Table S6
Video S1
Video S2
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.