Patients and clinical examination

A total of 80 patients with CIDP treated in St Josef-Hospital, University Hospital Bochum, Germany between June 2019 and April 2020 were included in the present study. The ethics committee of the Ruhr University Bochum approved the study (prospective Immunmediated Neuropathies Biobank [INHIBIT; vote-no. 18-6534-BR]). Diagnosis of CIDP was made according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria [1]. For diagnosis of atypical CIDP, including distal acquired demyelinating symmetric (DADS) neuropathy and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), the criteria reported by Doneddu et al. [6] were used in addition to EFNS/PNS criteria.

Clinical examination included neurological examination and assessment of Medical Research Council (MRC) score [7] for the following muscles: deltoid, biceps, wrist extensor, finger abductor, iliopsoas, quadriceps femoris, tibialis anterior, and big toe extensor. MRC sum score was calculated from those muscles described by the MRC [7]. Disability was recorded using the Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT-ODSS) [8], with separate recording of arm and leg score as well as sum score.

Muscle ultrasonography

Muscle ultrasonography was performed using an Affinity^® 70G ultrasound system (Philips, Hamburg, Germany) with an 18-MHz linear array transducer. Ultrasound settings (e.g., contrast), excluding depth and focus, were kept constant during all examinations. The following muscles were examined on both sides: the abductor pollicis brevis (APB; between carpometacarpal joint and metacarpophalangeal joint, longitudinal section); abductor digiti minimi (ADM; between wrist and finger root, longitudinal section); extensor carpi radialis longus (ECR; at level of elbow joint, cross section), biceps brachii (BB; distal third to middle of the upper arm, cross section), triceps brachii (TB; middle of the upper arm, cross section), rectus femoris (RF; distal third of thigh, cross section); tibial anterior muscle (TA; proximal third of the lower leg, cross section); and medial head of gastrocnemius muscle (GM; proximal third of the lower leg, cross section). Muscle echointensity was graded using the Heckmatt scale, which ranges from 1 (normal echointensity) to 4 (increased echointensity), according to Heckmatt et al.[9]

Additionally, we counted the number of fasciculations detected by MUS in 30 s. For some analyses muscles were arranged into the following groups: proximal arm muscles: BB, TB; distal arm muscles: APB, ADM, ECR; proximal leg muscle: RF; and distal leg muscles: TA, GM.

In a few patients, not all muscles from both sides could be examined (due to peripheral venous catheter), so that the number of patients was reduced to approximately 75 patients, depending on analysis. The numbers of patients included in each analysis are provided in the results and tables accordingly.

Electromyography

To validate the suitability of MUS to detect fasciculations in CIDP, we compared fasciculations detected by ultrasonography with fasciculations detected by electromyography (EMG), the "gold standard" for detecting fasciculations in neuromuscular disease.

Needle EMG was performed by a blinded examiner with a Dantec™ Keypoint^® G4 four-channel EMG device (Natus Europe GmbH, Planegg, Germany) and a corresponding disposable concentric monopolar needle electrode 50 × 0.46 mm, with a 0.07-mm² recording area (Value Line DCN, Natus, Ireland) as described by Stöhr et al. [10]. The number of fasciculations were sampled in the TA in 10 different needle locations, each observed for 10 s. EMG was performed independently of this study. After power analysis using G*Power (version 3.1.9.6; Heinrich-Heine-Universität Düsseldorf, Germany) determining that 13 patients would be needed to depict a correlation with r = 0.7, p ≤ 0.05 and a power of 0.8, we analysed the EMG results for 15 patients.

Statistics

Clinical and ultrasound data were compared between patients with typical and atypical CIDP using the t-test (for parametric variables) or the Mann–Whitney U-test (for non-parametric variables) and the chi-squared test as applicable. Correlation analyses were performed using Spearman correlation. Statistical analysis was performed using IBM^® SPSS Statistics (version 26.0.0.0; IBM Deutschland GmbH, Ehningen, Germany). For all analyses, the statistically significant threshold was set at p <0.05.

Characteristics of patients

Of the 80 CIDP patients, 40 had typical and 40 had atypical CIDP. Of atypical CIDP, 20 patients had DADS neuropathy, 10 had MADSAM and 10 had other atypical CIDP-like pure sensory, pure motor or acute-onset CIDP. Diagnosis according to EFNS/PNS criteria was definite in 66 (83%), probable in five (6%) and possible in nine patients (11%).

Table 1 shows the baseline characteristics of all patients and typical and atypical CIDP. Disease duration from first symptoms and from diagnosis to examination did not differ between the groups, but time between first symptoms to diagnosis was longer in atypical CIDP patients. Pure sensory symptoms without motor impairment at diagnosis was more frequent in atypical CIDP. At the time of examination, atypical CIDP patients were less disabled, according to INCAT-ODSS and MRC sum score, than typical CIDP patients (Figure 1).

Of the 80 patients, 78 received immunotherapy. Two patients had no treatment as their disease was stable after initial treatment and immunotherapy could be stopped. First-line therapy with corticosteroids or immunoglobulins was applied in 62 of 80 patients. Plasma exchange was not performed. Details on treatments are given in Table 1. Applied treatments were not statistically different between the typical and atypical CIDP groups.

Distribution of alterations of echointensity

Most alterations of echointensity were detected in the distal leg muscles (median [range] Heckmatt score for distal leg muscles 1.5 [1–4]). Figure 2 (right part) shows the histograms of Heckmatt scores for each muscle. Only eight of 1269 examined muscles had a Heckmatt score of 4 (TA and GM). Figure 3 shows examples of two patients with Heckmatt scores 1 and 4 for the TA.

There were no differences between typical and atypical CIDP patients regarding number of fasciculations or Heckmatt score (Table S1).

Heckmatt scores for arm and leg muscles correlates with disability and muscle strength

Arm score of the INCAT-ODSS correlated to Heckmatt score for the distal arm muscles (r = 0.23, p = 0.046) and leg score of the INCAT-ODSS correlated to Heckmatt scores for the proximal (r = 0.34, p = 0.002) and distal leg muscles (r = 0.33, p = 0.004; Figure 4a–c).

The MRC sum score, as well as the individual MRC arm and leg muscle scores, correlated to Heckmatt scores for the corresponding muscle groups (r = −0.25, p = 0.02 for MRC sum score and proximal arm muscle Heckmatt scores; r = −0.21, p = nonsignificant for MRC sum score and distal arm muscle Heckmatt scores; r = −0.35, p = 0.002 for MRC sum score and proximal leg muscle Heckmatt scores; r = −0.35, p = 0.002 for MRC sum score and distal leg muscle Heckmatt scores). Regarding MRC score for each individual muscle and Heckmatt scores for the same muscle, we found correlations mainly for the distal muscles of the arms and legs (Table S2).

Intra- and interrater reliability of echointensity analysis using the Heckmatt scale

Cronbach's alpha, reflecting intrarater reliability, was 0.95 for Examiner 1 (A.F.), 0.95 for Examiner 2 (S.F.) and 0.97 for Examiner 3 (Z.S.), resulting in an excellent intrarater reliability for analyzing echointensity using the Heckmatt scale.

The intraclass correlation coefficient, reflecting interrater reliability, was 0.82, which was considered to indicate good interrater reliability for analyzing echointensity using the Heckmatt scale.

Distribution of fasciculations

Fasciculations were most frequent in the distal leg muscles (mean 3.0 ± 4.5 per 30 s) and least frequent in the proximal leg muscles (mean 0.7 ± 1.9 per 30 s). In the arm muscles, fasciculations also occurred more often distally than proximally. In most cases, fasciculations occurred simultaneously in the arm and leg muscles and were rarely isolated in the proximal muscles (Table 2). Overall, fasciculations were found in 81% of all patients. The frequency of fasciculations for each muscle group is shown in Figure 2 (left panel).

Number of fasciculations found on MUS correlate to those found on EMG

The number of fasciculations of the TA measured by MUS correlated to the number of fasciculations of the TA measured in EMG (r = 0.6, p = 0.03; Figure 4d).