Abstract

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased threshold change in threshold electrotonus in both hyperpolarizing and depolarizing directions [depolarizing threshold electrotonus (90–100 ms) P < 0.005, hyperpolarizing threshold electrotonus (10–20 ms), P < 0.01, hyperpolarizing threshold electrotonus (90–100 ms), P < 0.05], perhaps suggesting early hyperpolarization. In addition, using excitability parameters superexcitability, subexcitability and hyperpolarizing threshold electrotonus (10–20 ms), the patients with acute inflammatory demyelinating polyneuropathy and acute-onset chronic inflammatory demyelinating polyneuropathy could be clearly separated into two non-overlapping groups. Studies of nerve excitability may be able to differentiate acute from acute-onset chronic inflammatory demyelinating polyneuropathy at an early stage. Characteristic nerve excitability parameter changes occur in early acute-onset chronic inflammatory demyelinating polyneuropathy, to match the clinical phenotype. Importantly, this pattern of change was strikingly different to that shown by patients with acute inflammatory demyelinating polyneuropathy, suggesting that nerve excitability techniques may be useful in distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy at the initial stage.

Introduction

Acute inflammatory demyelinating polyneuropathy (AIDP) is characterized by a monophasic course, with a clinical nadir within 4 weeks of symptom onset (Van der Meché et al., 2001). By contrast, chronic inflammatory demyelinating polyneuropathy (CIDP) typically demonstrates a slowly progressive course with gradual worsening over more than an 8-week period, with relapsing symptoms (Asbury and Cornblath, 1990). However, up to 16% of patients with CIDP may demonstrate acute-onset CIDP, characterized by a rapidly progressive onset within 8 weeks (McCombe et al., 1987; Ruts et al., 2010). Distinguishing patients with AIDP and acute-onset CIDP has been a challenging clinical issue, especially for patients presenting early in the course of disease, where differentiation has not been possible (Odaka et al., 2003). Although diagnostic criteria are available for both diseases (Absury and Cornblath, 1990; Van den Bergh et al., 2010), a patient may only be classified as having acute-onset CIDP with certainty after progression or relapse occurs 8 weeks after initial neurological symptoms. With the likely institution of immunotherapy that typically occurs in such patients early in the disease course, including intravenous immunoglobulin or plasma exchange, it becomes even more difficult to establish the correct diagnosis, as the early institution of therapy may initially prevent symptomatic progression (Odaka et al., 2003; Yuki and Hartung, 2012).

Nevertheless, an early and accurate diagnosis of patients with AIDP or acute-onset CIDP has significant prognostic and treatment implications. Patients with acute-onset CIDP require maintenance therapy to prevent relapse. Several previous studies have been undertaken to provide clinicians with more clues for early differentiation of the two diseases by clinical presentation and routine nerve conduction study results, but the availability of a more accurate diagnostic tool is clearly needed to predict the risk of relapse in patients (Dionne et al., 2010; Ruts et al., 2010).

The nerve excitability test, a technique that uses threshold tracking to measure peripheral nerve function, has been developed to provide additional information regarding axonal ion channel function and the resting membrane potential in a clinical setting. The nerve excitability test has previously been used to study both AIDP and CIDP patients, identifying a pattern of abnormalities characteristic of CIDP (Cappelen-Smith et al., 2000; Sung et al., 2004; Lin et al., 2011). In contrast to CIDP, nerve excitability test findings in patients with AIDP have tended to be less well defined (Kuwabara et al., 2002), akin to the clinical variability of the underlying disease process. Despite the available knowledge on nerve excitability test patterns of AIDP and CIDP, the potential diagnostic use of nerve excitability tests to predict AIDP and CIDP early in the course of the disease has not been investigated. In the present study, we attempt to elucidate the capability of nerve excitability tests to distinguish AIDP and acute-onset CIDP, to better guide therapeutic approaches.

Materials and methods

Patients

Patients were prospectively recruited in a consecutive fashion from the Wan Fang Hospital, Taipei, Taiwan, and Prince of Wales Hospital, Sydney, Australia. Patients with additional conditions that might cause neuropathy, such as diabetes mellitus or malignancy, and those with evidence of carpal tunnel syndrome or cervical radiculopathy determined by nerve conduction studies or cervical spine imaging, were excluded. The diagnosis of AIDP was determined based on clinical features and in accordance with current Guillain-Barré syndrome diagnostic criteria as proposed by Asbury and Cornblath (1990) with AIDP electrodiagnostic criteria as developed by Ho et al. (1995). Patients subsequently diagnosed with acute motor axonal neuropathy, acute sensorimotor axonal polyneuropathy, acute pan-dysautonomia and Miller Fisher syndrome were excluded (Ho et al., 1995; Panda and Tripathi, 2002).

For a patient to be classified with AIDP, the time from onset to peak of symptoms was defined as <4 weeks without further relapse or worsening of symptoms observed during clinical follow-up. Acute-onset CIDP was diagnosed when a patient initially diagnosed as AIDP eventually met the clinical and electrodiagnostic criteria for definite CIDP, as defined by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) (Van den Bergh et al., 2010). Patients in this cohort had initially presented within 4 weeks of symptom onset, but subsequently deteriorated or relapsed after 8 weeks, or had three or more episodes of deterioration (Ruts et al., 2010).

Control data for nerve excitability tests were obtained from 117 healthy subjects, and divided into two age cohorts, HC1 with mean age of 50.0 ± 2.4 years (n = 81), and HC2 with mean age of 34.4 ± 1.6 years (n = 36). All subjects gave informed consent to the procedures, and the study was approved by the ethics committees of the Taipei Medical University School of Medicine and the University of New South Wales.

Study design

Patients were identified within 8 weeks of symptom onset and clinical functional grading and routine nerve conduction studies were obtained upon enrolment in the study. Nerve excitability tests were performed within 8 weeks of symptom onset, and before the institution of immunotherapy treatment. Patients were followed-up longitudinally for at least 1 year after the initial acute episode to identify any deterioration or relapses.

Clinical functional grading and patient follow-up

The Medical Research Council (MRC) sum scores (Kleyweg et al., 1991) for grading muscle power were assessed for the following muscle pairs: upper arm abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsal flexors. Clinical disabilities were also evaluated, using the Hughes functional grading scale (Hughes et al., 1978) (Grade 1, minor symptom and signs, able to run; Grade 2, able to walk 5 m without aids; Grade 3, able to walk 5 m with aids; Grade 4, chair- or bed-bound; Grade 5, requiring assisted ventilation).

Nerve excitability testing

Nerve excitability studies were undertaken on the median nerve, stimulating over the median nerve at the wrist and recording compound muscle action potentials from the abductor pollicis brevis, as per previously detailed protocols (Kiernan et al., 2000). Stimulation and recording were controlled by software (QTRAC; Institute of Neurology, London, UK) and stimulus current was applied using an isolated linear bipolar constant-current stimulator (DS5; Digitimer). The changes in current required to produce a target potential corresponding to 40% of the maximal compound muscle action potential were tracked.

The nerve excitability test protocol incorporated the following measures: (i) a stimulus response curve; (ii) strength-duration relationship; (iii) threshold electrotonus (TE) using subthreshold 100-ms polarizing currents in both depolarizing (TEd; +40%) and hyperpolarizing (TEh; −40%) directions to alter the potential difference across the internodal membrane; and (iv) recovery cycle using a paired pulse paradigm with a supramaximal conditioning stimulus followed by a test stimulus at interstimulus intervals from 2 to 200 ms. Superexcitability was measured as the maximal threshold reduction, and subexcitability as the maximal threshold increase after an interstimulus interval of 10 ms. Relative refractory period (RRP) was measured as the time of first intercept on the x-axis of the recovery cycle curve.

Latency was defined as the time delay (ms) between stimulus onset and peak compound muscle action potential response. Stimulus threshold was defined as the current (mA) required to produce a compound muscle action potential response of half maximal amplitude. Skin temperature was monitored at the site of stimulation and was maintained above 32°C.

Statistical analysis

Nerve excitability indices of patients with AIDP, patients with acute-onset CIDP, and control subjects were compared with unpaired t-test or Mann-Whitney U-test depending on normality (assessed using the Lilliefors’ test), using QTracP (Institute of Neurology) software. All data are presented as mean ± standard error of the mean, except latency, stimulus threshold and rheobase which are presented as geometric means.

Results

Clinical profiles

A total of 22 patients were recruited in the present study. Of these patients, six eventually fulfilled diagnostic criteria for acute-onset CIDP due to further deterioration in the follow-up period. Of these, two patients were excluded from analysis (one due to diabetes mellitus and one due to nerve excitability testing after the onset of immunotherapy). The remaining patients did not suffer from recurrent symptoms, compatible with the diagnosis of AIDP. However, three were excluded from analysis due to their subsequent diagnosis with Miller-Fisher syndrome or acute pan-dysautonomia variants of Guillain-Barré syndrome. Two further patients were excluded due to co-existent diabetes mellitus and one patient was excluded who received nerve excitability test examination after commencement of immunotherapy. The demographic and clinical profiles of the analysed patient cohort (10 AIDP, four acute-onset CIDP) are summarized in Table 1.

Table 1

Patient clinical profile

Patient classification Patient No. Sex Age at onset Days between onset and NETa Hughes gradeb MRCc sum score 
AIDP 36 18 56 
44 46 
63 58 
56 51 
62 35 58 
56 45 
70 15 42 
48 12 52 
69 46 
10 46 52 
A-CIDP 66 36 48 
17 58 
24 58 
32 29 55 
Patient classification Patient No. Sex Age at onset Days between onset and NETa Hughes gradeb MRCc sum score 
AIDP 36 18 56 
44 46 
63 58 
56 51 
62 35 58 
56 45 
70 15 42 
48 12 52 
69 46 
10 46 52 
A-CIDP 66 36 48 
17 58 
24 58 
32 29 55 

MRC = Medical Research Council; NET = nerve excitability testing. A-CIDP = acute-onset CIDP.

a Days between onset of symptoms and nerve excitability testing.

b 1, minor symptom and signs, able to run; 2, able to walk 5 m without aids; 3, able to walk 5 m with aids; 4, unable to walk; 5, requiring assisted ventilation.

c The MRC sum scores for grading muscle power were assessed for the following muscle pairs: upper arm abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsal flexors. Each muscle was graded with a maximum of 5 for a total maximal score of 60.

Clinical severity as evaluated by MRC sum score and Hughes grade were not significantly different between the AIDP and acute-onset CIDP cohorts [Hughes grade AIDP 2.5 ± 0.3, acute-onset CIDP 2.3 ± 0.8; not significant (n.s.); MRC sum score AIDP 50.6 ± 1.8, acute-onset CIDP 54.8 ± 2.4; n.s.]. There was also no difference in terms of time between onset of initial symptoms and nerve excitability tests assessment between the two cohorts (AIDP 11.6 ± 3.0 days; acute-onset CIDP 19 ± 7.9 days; n.s.). In addition, there were no significant differences in conventional nerve conduction study parameters as derived from the median nerve (median motor amplitude AIDP 6.6 ± 1.6 mV; acute-onset CIDP 5.6 ± 1.0 mV; n.s.; median conduction velocity AIDP 47.3 ± 2.6 m/s; acute-onset CIDP 49.5 ± 1.6 m/s; n.s.). However, patients with AIDP were significantly older than patients with acute-onset CIDP (AIDP 55.4 ± 3.5 years, acute-onset CIDP 34.8 ± 10.9 years, P < 0.05).

Comparison of nerve excitability indices

Latency, stimulus-response and strength-duration properties

Due to the age difference between patients with AIDP and acute-onset CIDP, two cohorts of age-matched healthy controls HC1 and HC2 were used for data analysis (Table 2). In comparison with age-matched healthy controls (HC1), patients with AIDP demonstrated significantly prolonged latencies (P < 0.001, Table 2), increased threshold for 50% compound muscle action potential (P < 0.001) and increased rheobasic current (Fig. 1A, P < 0.001). In the acute-onset CIDP cohort, latencies were also prolonged compared to age-matched healthy controls (HC2) (P < 0.001, Table 2), but there was no significant increase in the rheobasic current (n.s., Table 2) or in the stimulus threshold for 50% compound muscle action potential (n.s., Table 2). Strength-duration time constant was not significantly altered in either cohort (Fig. 1B, AIDP 0.45 ± 0.03 ms; acute-onset CIDP 0.46 ± 0.1 ms; HC1 0.43 ± 0.01 ms, HC2 0.42 ± 0.01 ms, n.s.).

Figure 1

Nerve excitability profiles of patients with AIDP and CIDP compared to age-matched controls. Two age-matched control groups were obtained, to match the age of patients with AIDP (HC1) and patients with acute-onset CIDP (HC2), respectively. AIDP is plotted with open circles, acute-onset CIDP (A-CIDP) with filled circles, HC1 with a thick line and HC2 with a grey line. (A) Stimulus response curves, demonstrating increased threshold for 50% compound muscle action potential in patients with AIDP. (B) Stimulus charge plot. Rheobase is the slope of the line and the x-intercept is equivalent to the strength duration time constant. (C) Threshold electrotonus—response to 100 ms current pulse (subthreshold ± 40% of threshold current) with depolarizing threshold electrotonus in the top quadrant and hyperpolarizing threshold electrotonus in the lower section. (D) Recovery cycle of excitability following an impulse with characteristic phases of refractoriness, superexcitability and subexcitability.

Figure 1

Nerve excitability profiles of patients with AIDP and CIDP compared to age-matched controls. Two age-matched control groups were obtained, to match the age of patients with AIDP (HC1) and patients with acute-onset CIDP (HC2), respectively. AIDP is plotted with open circles, acute-onset CIDP (A-CIDP) with filled circles, HC1 with a thick line and HC2 with a grey line. (A) Stimulus response curves, demonstrating increased threshold for 50% compound muscle action potential in patients with AIDP. (B) Stimulus charge plot. Rheobase is the slope of the line and the x-intercept is equivalent to the strength duration time constant. (C) Threshold electrotonus—response to 100 ms current pulse (subthreshold ± 40% of threshold current) with depolarizing threshold electrotonus in the top quadrant and hyperpolarizing threshold electrotonus in the lower section. (D) Recovery cycle of excitability following an impulse with characteristic phases of refractoriness, superexcitability and subexcitability.

Table 2

Excitability indices for AIDP and A-CIDP versus healthy control cohorts

   AIDP  HC1 Unpaired t-test  A-CIDP  HC2 Unpaired t-test 
Excitability properties Excitability indices     Mean ± SE  (n = 10)     Mean ± SE  (n = 81) AIDP versus HC1     Mean ± SE (n = 4)     Mean ± SE (n = 36) A-CIDP versus HC2 

 
 Age (years) 55.4 ± 3.5 49.9 ± 2.3 NS 34.8 ± 11 34.4 ± 1.6 NS 
 Latency (ms) 13.3 ± 2.1 6.6 ± 0.1 P < 0.001*** 7.5 ± 0.4 6.4 ± 0.1 P < 0.001*** 
 Stimulus (mA) for 50% CMAP 7.3 ± 1.3 3.5 ± 1.1 P < 0.001*** 4.6 ± 1.6 3.4 ± 1.1 NS 
Rheobase (mA) 4.7 ± 1.3 2.3 ± 1.1 P < 0.001*** 3.1 ± 1.7 2.3 ± 1.1 NS 
Recovery cycle 
 RRP (ms) 3.9 ± 1.1 3.1 ± 1.0 P ≤ 0.001*** 2.96 ± 1.2 3.04 ± 1.0 NS 
Superexcitability (%)  − 17.3 ± 2.8 −24.3 ± 0.7 P < 0.005** −31.9 ± 3.2 −26.6 ± 0.8 P < 0.05* 
Subexcitability (%) 15.7 ± 1.5 14.6 ± 0.4 NS 10.7 ± 1.1 15.2 ± 0.7 P < 0.05* 
Threshold electrotonus 
 TEd(10–20 ms) 67.0 ± 2.2 68.3 ± 0.6 NS 72.8 ± 3.7 67.8 ± 0.7 P < 0.05* 
TEd(90–100 ms) 44.6 ± 2.4 45.1 ± 0.4 NS 52.2 ± 4.3 45.1 ± 0.5 P < 0.005** 
TEh(10–20 ms) −78.6 ± 4.8 −74.2 ± 0.6 NS −83.7 ± 8.7 −72.8 ± 0.9 P < 0.001*** 
TEh(90–100 ms) −127.6 ± 13 −119.0 ± 1.9 NS −155.3 ± 28.2 −118.4 ± 2.4 P < 0.005** 
   AIDP  HC1 Unpaired t-test  A-CIDP  HC2 Unpaired t-test 
Excitability properties Excitability indices     Mean ± SE  (n = 10)     Mean ± SE  (n = 81) AIDP versus HC1     Mean ± SE (n = 4)     Mean ± SE (n = 36) A-CIDP versus HC2 

 
 Age (years) 55.4 ± 3.5 49.9 ± 2.3 NS 34.8 ± 11 34.4 ± 1.6 NS 
 Latency (ms) 13.3 ± 2.1 6.6 ± 0.1 P < 0.001*** 7.5 ± 0.4 6.4 ± 0.1 P < 0.001*** 
 Stimulus (mA) for 50% CMAP 7.3 ± 1.3 3.5 ± 1.1 P < 0.001*** 4.6 ± 1.6 3.4 ± 1.1 NS 
Rheobase (mA) 4.7 ± 1.3 2.3 ± 1.1 P < 0.001*** 3.1 ± 1.7 2.3 ± 1.1 NS 
Recovery cycle 
 RRP (ms) 3.9 ± 1.1 3.1 ± 1.0 P ≤ 0.001*** 2.96 ± 1.2 3.04 ± 1.0 NS 
Superexcitability (%)  − 17.3 ± 2.8 −24.3 ± 0.7 P < 0.005** −31.9 ± 3.2 −26.6 ± 0.8 P < 0.05* 
Subexcitability (%) 15.7 ± 1.5 14.6 ± 0.4 NS 10.7 ± 1.1 15.2 ± 0.7 P < 0.05* 
Threshold electrotonus 
 TEd(10–20 ms) 67.0 ± 2.2 68.3 ± 0.6 NS 72.8 ± 3.7 67.8 ± 0.7 P < 0.05* 
TEd(90–100 ms) 44.6 ± 2.4 45.1 ± 0.4 NS 52.2 ± 4.3 45.1 ± 0.5 P < 0.005** 
TEh(10–20 ms) −78.6 ± 4.8 −74.2 ± 0.6 NS −83.7 ± 8.7 −72.8 ± 0.9 P < 0.001*** 
TEh(90–100 ms) −127.6 ± 13 −119.0 ± 1.9 NS −155.3 ± 28.2 −118.4 ± 2.4 P < 0.005** 

CMAP = compound muscle action potential; NS = not statistically significant; RRP = relative refractory period; A-CIDP = acute-onset CIDP.

Recovery cycle of excitability

In the patients with AIDP, the mean recovery cycle curve was shifted upwards compared to HC1, with significantly reduced superexcitability (P < 0.001, Table 2, Figs 1D and 2) and prolonged relative refractory period (P < 0.01, Table 2). However, subexcitability was not significantly altered (Table 2). In contrast, in the patients with acute-onset CIDP, the mean recovery cycle demonstrated an opposite pattern of change, with significant increased superexcitability (P < 0.05, Table 2) and decreased subexcitability (P < 0.05, Table 2), although relative refractory period and refractoriness were not significantly altered.

Figure 2

Recovery cycles parameters in patients with AIDP and acute-onset CIDP (A-CIDP), with left panels showing patients with AIDP (filled bars) compared to healthy controls (HC1; open bars) and right panels showing acute-onset CIDP (hatched bars) and healthy controls (HC2; open bars). (A) Relative refractory period (RRP) demonstrating increased relative refractory period in patients with AIDP. (B) Superexcitability was reduced in AIDP and increased in acute-onset CIDP relative to controls. (C) Subexcitability was decreased in acute-onset CIDP. NS = not significant. *P < 0.05; **P < 0.005; ****P < 0.001.

Figure 2

Recovery cycles parameters in patients with AIDP and acute-onset CIDP (A-CIDP), with left panels showing patients with AIDP (filled bars) compared to healthy controls (HC1; open bars) and right panels showing acute-onset CIDP (hatched bars) and healthy controls (HC2; open bars). (A) Relative refractory period (RRP) demonstrating increased relative refractory period in patients with AIDP. (B) Superexcitability was reduced in AIDP and increased in acute-onset CIDP relative to controls. (C) Subexcitability was decreased in acute-onset CIDP. NS = not significant. *P < 0.05; **P < 0.005; ****P < 0.001.

Threshold electrotonus

In patients with AIDP, there was no significant change in threshold electrotonus noted in comparison with HC1. However, in the patients with acute-onset CIDP, there were a number of significant changes in threshold electrotonus in both hyperpolarizing and depolarizing directions [Figs 1 and 3, Table 2, TEd(90–100 ms) P < 0.005, TEh(10–20 ms), P < 0.01, TEh(90–100 ms), P < 0.05]. Overall, patients with acute-onset CIDP demonstrated significantly greater threshold change when compared to normal, particularly in the hyperpolarizing direction, reflecting the significant difference in the accommodation properties.

Early identification using nerve excitability parameters

Importantly, nerve excitability parameters can be used to separate patients with acute-onset CIDP from patients with AIDP at an early stage of the disease, before commencement of immunotherapy. The changes in superexcitability and subexcitability between AIDP and acute-onset CIDP patients are quite distinct, and a combination of these two recovery cycle parameters enabled the separation of patients with AIDP and acute-onset CIDP into two groups (Fig. 4A). Further, separation of distinct patient groups could also be achieved by combining threshold electrotonus parameters [TEd(10–20) ms] with recovery cycle parameters (superexcitability at 7 ms; Fig. 4B) with no overlap between patient groups. These findings highlight the potential use of nerve excitability tests in the early identification of acute-onset CIDP patient cohorts.

Figure 3

TE parameters in patients with AIDP and acute-onset CIDP (A-CIDP), with left panels showing patients with AIDP (filled bars) compared to healthy controls (HC1; open bars) and right panels showing acute-onset CIDP (hatched bars) and healthy controls (HC2; open bars). (A) Threshold electrotonus after 10–20 ms of depolarizing current [TEd(10–20 ms)]. (B) Threshold electrotonus after 90–100 ms of depolarizing current [TEd(90–100 ms)]. (C) Threshold electrotonus after 90–100 ms of hyperpolarizing current [TEh(90–100 ms)]. Patients with acute-onset CIDP demonstrated significant differences compared to healthy controls in threshold electrotonus parameters but patients with AIDP did not differ from controls. *P < 0.05; **P < 0.005.

Figure 3

TE parameters in patients with AIDP and acute-onset CIDP (A-CIDP), with left panels showing patients with AIDP (filled bars) compared to healthy controls (HC1; open bars) and right panels showing acute-onset CIDP (hatched bars) and healthy controls (HC2; open bars). (A) Threshold electrotonus after 10–20 ms of depolarizing current [TEd(10–20 ms)]. (B) Threshold electrotonus after 90–100 ms of depolarizing current [TEd(90–100 ms)]. (C) Threshold electrotonus after 90–100 ms of hyperpolarizing current [TEh(90–100 ms)]. Patients with acute-onset CIDP demonstrated significant differences compared to healthy controls in threshold electrotonus parameters but patients with AIDP did not differ from controls. *P < 0.05; **P < 0.005.

Figure 4

Plot dissociating patients with AIDP from acute-onset CIDP using two nerve excitability parameters. Blue filled circles represent individual values for patients with AIDP and red filled circles are patients with acute-onset CIDP. (A) The excitability parameters subexcitability and superexcitability are plotted on each axis and the dotted line represents the cut-off between AIDP and acute-onset CIDP patients. (B) A similar plot of threshold electrotonus after 10–20 ms of depolarizing current [TEd(10–20 ms)] and superexcitability.

Figure 4

Plot dissociating patients with AIDP from acute-onset CIDP using two nerve excitability parameters. Blue filled circles represent individual values for patients with AIDP and red filled circles are patients with acute-onset CIDP. (A) The excitability parameters subexcitability and superexcitability are plotted on each axis and the dotted line represents the cut-off between AIDP and acute-onset CIDP patients. (B) A similar plot of threshold electrotonus after 10–20 ms of depolarizing current [TEd(10–20 ms)] and superexcitability.

Discussion

The present study investigated whether changes in membrane excitability were evident between patients with AIDP and acute-onset CIDP to enable these conditions to be differentiated at an early stage. Identification of a marker of acute-onset CIDP would enable early diagnosis and would therefore facilitate therapeutic decisions. The present study has established a distinct pattern of membrane dysfunction in patients with acute-onset CIDP within 40 days of symptom onset and before the implementation of immunotherapy. Importantly, this pattern of excitability change was significantly different to that demonstrated in patients with AIDP, suggesting that nerve excitability tests could differentiate patients, prior to relapse. The present findings also raise the suggestion that different pathophysiological processes may be developing at the level of axonal membrane, despite AIDP and acute-onset CIDP excitability appearing similar at the initial clinical presentation.

Diagnosis of acute onset chronic inflammatory demyelinating polyneuropathy

Although both AIDP and CIDP are immune-related neuropathies, they are differentiated by disease course and time course of nadir. Conventional nerve conduction studies are limited in their ability to differentiate these patient groups in initial stages. Previous studies that attempted to differentiate AIDP and acute-onset CIDP cohorts have failed to find significant neurophysiological differences with conventional nerve conduction study, in line with results from the present study (Dionne et al., 2010; Ruts et al., 2010). Previous findings suggested a trend towards reduced conduction velocity in patients with acute-onset CIDP but overall the neurophysiological profile was not clearly different (Dionne et al., 2010; Ruts et al., 2010). Clinically, patients with acute-onset CIDP demonstrated reduced symptomatic severity, less cranial nerve dysfunction and were less likely to require ventilation (Dionne et al., 2010; Ruts et al., 2010). However, none of these features have been demonstrated to be specific for acute-onset CIDP.

An outstanding question remains—how much of a clinical deterioration would alter the diagnosis from AIDP to acute-onset CIDP? Others have concluded that the diagnosis of acute-onset CIDP should be suspected when patients initially diagnosed with AIDP, have three or more clinical deteriorations or when they have a subsequent deterioration 8 weeks after the onset of symptoms (Fig. 5). It remains important to look for these secondary deteriorations as patients with AIDP may improve after a further course of intravenous immunoglobulin whereas some of these patients may yet turn out to have a variant of acute-onset CIDP, needing chronic maintenance treatment (Van Doorn, 2013). As such, identification of a nerve excitability test biomarker of acute-onset CIDP would be ideally incorporated into the clinical profile of this patient cohort.

Figure 5

Top: Weakness versus time from onset: schematic diagram depicting the characteristic pattern of patient weakness from the onset of symptoms in patients with AIDP and acute-onset CIDP (A-CIDP). Typical changes in response to immunotherapy treatment are depicted. Bottom: Diagnostic diagram demonstrating the rational for using nerve excitability testing to assist with diagnosis and follow up of patients.

Figure 5

Top: Weakness versus time from onset: schematic diagram depicting the characteristic pattern of patient weakness from the onset of symptoms in patients with AIDP and acute-onset CIDP (A-CIDP). Typical changes in response to immunotherapy treatment are depicted. Bottom: Diagnostic diagram demonstrating the rational for using nerve excitability testing to assist with diagnosis and follow up of patients.

Nerve excitability testing in inflammatory neuropathies

The present study is the first to compare peripheral nerve excitability in patients with acute-onset CIDP with patients with AIDP within 40 days of symptom onset and before treatment. Previous studies have identified a similar nerve excitability test profile in patients with established CIDP, with increased threshold change in threshold electrotonus (Cappelen-Smith et al., 2000; Sung et al., 2004; Lin et al., 2011). The identified changes in nerve excitability tests in acute-onset CIDP and established CIDP are similar to those expected with paranodal and intermodal demyelination, consistent with mathematical modelling (Stephanova and Daskalova, 2005a, b). Further, CIDP is pathologically characterized by co-existent de- and remyelination (Van Den Burgh et al., 2010), and reduced internodal length is a feature of remyelinating axons. Accordingly, the excitability changes in patients with acute-onset CIDP were also similar to those reported in axons with shortened internodes (Moldovan et al., 2004). In addition, nerve excitability test changes have been attributed to axonal hyperpolarization due to similarities in nerve excitability test profile patterns to those demonstrated with membrane potential change (Kiernan et al., 2000). Such hyperpolarization has been related to Na+/K+ pump dysfunction, leading to potential imbalance of ionic fluxes.

Previous nerve excitability test studies have revealed a spectrum of changes associated with CIDP in peripheral excitability. For instance, it was demonstrated that patients with CIDP with greater changes in threshold electrotonus waveforms were more severely clinically affected and this pattern was associated with diffuse demyelination (Sung et al., 2004). However, patients with CIDP also demonstrated greater variability in nerve excitability test parameters (Cappelen-Smith et al., 2000; Sung et al., 2004). Prior to monthly maintenance treatments, CIDP patients demonstrated increased threshold change in threshold electrotonus and increased superexcitability, which normalized with intravenous immunoglobulin (Lin et al., 2011). Such rapid and cyclic improvement with immunotherapy treatment is suggestive of a functional rather than structural basis for ongoing symptoms.

In contrast, previous studies have not demonstrated major excitability changes in AIDP (Cappelen-Smith et al., 2000; Sung et al., 2004). This has been attributed to a lack of generalized nerve dysfunction in AIDP or in other words, patchy involvement along the course of the nerve at the molecular level. Nodal adhesion proteins have been identified as target antigens in immune-related polyneuropathy (Yuki and Hartung, 2012), suggesting that physiological changes may start from the nodal and juxtaparanode area in some patients with AIDP. There is also increasing evidence that such early excitability changes may produce a conduction block in patients with AIDP, rather than structural changes. In addition, recent studies suggest that sera from patients with AIDP targets nodal epitopes in the PNS (Devaux et al., 2012). In further support, evidence from experimental allergic neuritis (EAN) models suggest that nodal changes may be more critical to pathophysiology and treatment response than changes occurring at the myelin level (Pollard and Armati, 2011). Thus, early changes in peripheral excitability, rather than demyelination per se, may influence disease identification and clinical progression in both AIDP and CIDP.

Potential pathophysiological mechanisms

The different nerve excitability test profiles established by the present study for patients with early AIDP compared to acute-onset CIDP suggest that the underlying pathophysiological processes may be different. Alternatively, the actual timing of onset of acute-onset CIDP and AIDP may differ—with acute-onset CIDP progressing more gradually than AIDP and acute-onset CIDP patients presenting at a later stage. Accordingly, nerve pathology may have been more advanced in patients with acute-onset CIDP at the time of the study and this may be reflected in the different nerve excitability profile. Early pathological changes in CIDP involving compact myelin stripping and phagocytosis have been reported (Comi et al., 2009; Pollard and Armati, 2011), suggesting that the initial immune attack is not only limited to nodal areas but also reaches the internodal region. Accordingly, in the acute-onset CIDP cohort, nerve excitability indices (increased changes in threshold electrotonus in both depolarizing and hyperpolarizing directions) associated with both nodal and internodal properties demonstrated changes.

A further possibility for the differences between AIDP and acute-onset CIDP excitability profiles may reflect the balance between demyelination and an altered axonal environment. In experimental EAN models, increased intra-axonal pressure and oedema may lead to ischaemic axonal damage (Powell et al., 1991). Similarly, pathological studies in AIDP have revealed evidence for endoneurial fluid pressure increase and widespread distribution of demyelination in peripheral nerves even within 60 days of symptom onset (Berciano et al., 2000). Nerve ischaemia has profound effects on membrane excitability, producing depolarization (Kiernan and Bostock, 2000). Accordingly, the effects of nerve ischaemia may counteract the any effects of demyelination on membrane potential in patients with AIDP (Lin et al., 2002; Han et al., 2009).

Changes in ion channel distribution and function may occur very early following demyelination. Typically Na+ channels are clustered at high density at the nodes of Ranvier, with surrounding insulation from the myelin sheath ensuring salutatory conduction (Ritchie and Rogart, 1977). However, following demyelination, nodal Na+ channels and associated proteins may redistribute along the exposed axon to safeguard conduction (Foster et al., 1980). Such changes in Na+ channel distribution could also affect nerve excitability profiles. In addition, exposure of juxtaparanodal fast K+ channels as a result of demyelination may act to reduce excitability, hyperpolarizing the axon (Chiu and Ritchie, 1981). This immune-related myelin damage and poor accommodation of internodal slow potassium channels could explain the increased threshold change in threshold electrotonus. In addition, redistribution of fast K+ channels along paranode might induce axonal hyperpolarization, compatible with previous reports in CIDP (Lin et al., 2011).

In terms of representative patient numbers (six patients with acute-onset CIDP out of total 22 patients = 27%), previous cohorts had identified 2–16% of CIDP patients may present acutely (Ruts et al., 2010, 5% Odaka et al., 2003, 2% McCombe et al., 1987, 16%), suggesting that acute-onset CIDP is a rare cohort. In terms of potential limitations, although there was a difference in age between the two patient cohorts, this may have influenced latency and produced a higher threshold current in patients with AIDP. However, the differences in excitability properties have been related to appropriate age-matched controls.

Conclusion

The present study has identified different patterns of nerve excitability in the early stage of two immune-mediated polyneuropathies, AIDP and acute-onset CIDP. The nerve excitability test parameters, superexcitability and threshold electrotonus, may be potentially useful indices to distinguish between patients with AIDP and acute-onset CIDP. The different nerve excitability test patterns between patient cohorts may suggest that the pathophysiological features underlying AIDP and CIDP are different, even in the early stages when clinical features are not sufficient to distinguish between disorders. These findings may also explain why the results of conventional nerve conduction studies are not able to differentiate patients due to early nodal involvement in both diseases.

In conclusion, nerve excitability indices, specifically superexcitability and threshold electrotonus, may assist in the early detection of ion channel dysfunction before the development of morphological changes, and may serve as a useful biomarker for early identification of patients with AIDP and acute-onset CIDP. Such early treatment (before 8 weeks from onset) can be administered to avoid the progression of the weakness in acute-onset CIDP, as depicted in Fig. 5 (AIDP with early treatment), compared to the traditional standard where time is the only guidance.

Funding

We are grateful to Centre of Excellence for Clinical Trial and Research in Neuroscience, funded by project DOH 102-TD-B-111-003, for providing statistical consultancy. This work was partially supported by Taipei Medical University - Wan Fang Hospital Research Grant 102-wf-eva-02. S.P. is the recipient of a RG Menzies Foundation/National Health and Medical Research Council of Australia (NHMRC) Training Fellowship (# 1016446) and M.K. was supported by NHMRC ForeFront Program Grant (# 1037746).

Abbreviations

    Abbreviations
  • A-CIDP

    acute onset chronic inflammatory demyelinating polyneuropathy

  • AIDP

    acute inflammatory demyelinating polyneuropathy

  • CIDP

    chronic inflammatory demyelinating polyneuropathy

  • RRP

    relative refractory period

  • TE

    threshold electrotonus

References

Asbury
AK
Cornblath
DR
Assessment of current diagnostic criteria for Guillain-Barre syndrome
Ann Neurol
 , 
1990
, vol. 
27
 (pg. 
S21
-
4
)
Berciano
J
García
A
Figols
J
Muñoz
R
Berciano
MT
Lafarga
M
Perineurium contributes to axonal damage in acute inflammatory demyelinating polyneuropathy
Neurology
 , 
2000
, vol. 
55
 (pg. 
552
-
9
)
Cappelen-Smith
C
Kuwabara
S
Lin
CS
Mogyoros
I
Burke
D
Activity-dependent hyperpolarization and conduction block in chronic inflammatory demyelinating polyneuropathy
Ann Neurol
 , 
2000
, vol. 
48
 (pg. 
826
-
32
)
Chiu
SY
Ritchie
JM
Evidence for the presence of potassium channels in the paranodal region of acutely demyelinated mammalian single nerve fibres
J Physiol
 , 
1981
, vol. 
313
 (pg. 
415
-
37
)
Comi
C
Osio
M
Ferretti
M
Mesturini
R
Cappellano
G
Chiocchetti
A
, et al.  . 
Defective Fas-mediated T-cell apoptosis predicts acute onset CIDP
J Peripher Nerv Syst
 , 
2009
, vol. 
14
 (pg. 
101
-
6
)
Devaux
JJ
Odaka
M
Yuki
N
Nodal proteins are target antigens in Guillian-Barre syndrome
J Peripher Nerv Syst
 , 
2012
, vol. 
17
 (pg. 
62
-
71
)
Dionne
A
Nicolle
MW
Hahn
AF
Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy
Muscle Nerve
 , 
2010
, vol. 
41
 (pg. 
202
-
7
)
Foster
RE
Whalen
CC
Waxman
SG
Reorganization of the axonal membrane of demyelinated nerve fibers: morphological evidence
Science
 , 
1980
, vol. 
210
 (pg. 
661
-
3
)
Han
SE
Boland
RA
Krishnan
AV
Vucic
S
Lin
CS
Kiernan
MC
Ischaemic sensitivity of axons in carpal tunnel syndrome
J Peripher Nerv Syst
 , 
2009
, vol. 
14
 (pg. 
190
-
200
)
Ho
TW
Mishu
B
Li
CY
Gao
CY
Cornblath
DR
Griffin
JW
, et al.  . 
Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies
Brain
 , 
1995
, vol. 
118
 
Pt 3
(pg. 
597
-
605
)
Hughes
RA
Newsom-Davis
JM
Perkin
GD
Pierce
JM
Controlled trial prednisolone in acute polyneuropathy
Lancet
 , 
1978
, vol. 
2
 (pg. 
750
-
3
)
Kiernan
MC
Bostock
H
Effects of membrane polarization and ischaemia on the excitability properties of human motor axons
Brain
 , 
2000
, vol. 
123
 
Pt 12
(pg. 
2542
-
51
)
Kiernan
MC
Burke
D
Andersen
KV
Bostock
H
Multiple measures of axonal excitability: a new approach in clinical testing
Muscle Nerve
 , 
2000
, vol. 
23
 (pg. 
399
-
409
)
Kleyweg
RP
van der Meché
FG
Schmitz
PI
Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome
Muscle Nerve
 , 
1991
, vol. 
14
 (pg. 
1103
-
9
)
Kuwabara
S
Ogawara
K
Sung
JY
Mori
M
Kanai
K
Hattori
T
, et al.  . 
Differences in membrane properties of axonal and demyelinating Guillain-Barré syndromes
Ann Neurol
 , 
2002
, vol. 
52
 (pg. 
180
-
7
)
Lin
CS
Krishnan
AV
Park
SB
Kiernan
MC
Modulatory effects on axonal function after intravenous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy
Arch Neurol
 , 
2011
, vol. 
68
 (pg. 
862
-
9
)
Lin
CS
Kuwabara
S
Cappelen-Smith
C
Burke
D
Responses of human sensory and motor axons to the release of ischaemia and to hyperpolarizing currents
J Physiol
 , 
2002
, vol. 
541
 
Pt 3
(pg. 
1025
-
39
)
McCombe
PA
Pollard
JC
McLeod
JG
Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases
Brain
 , 
1987
, vol. 
111
 
Pt 6
(pg. 
1617
-
30
)
Moldovan
M
Krarup
C
Mechanisms of hyperpolarization in regenerated mature motor axons in cat
J Physiol
 , 
2004
, vol. 
560
 
Pt 3
(pg. 
807
-
19
)
Odaka
M
Yuki
N
Hirata
K
Patients with chronic inflammatory demyelinating polyneuropathy initially diagnosed as Guillain-Barré syndrome
J Neurol
 , 
2003
, vol. 
250
 (pg. 
913
-
6
)
Panda
S
Tripathi
M
Anti-GQ1b IgG antibody syndrome: clinical and immunological range
J Neurol Neurosurg Psychiatr
 , 
2002
, vol. 
72
 (pg. 
418
-
9
)
Pollard
JD
Armati
PJ
CIDP- the relevance of recent advances in Schwann cell/axonal neurobiology
J Peripher Nerv Syst
 , 
2011
, vol. 
16
 (pg. 
15
-
23
)
Powell
HC
Myers
RR
Mizisin
AP
Olee
T
Brotoff
SW
Response of the axon and barrier endothelium to experimental allergic neuritis induced by autoreactive T cell lines
Acta Neuropathol
 , 
1991
, vol. 
82
 (pg. 
364
-
77
)
Ritchie
JM
Rogart
RB
Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath
Proc Natl Acad Sci USA
 , 
1977
, vol. 
74
 (pg. 
211
-
5
)
Ruts
L
Drenthen
J
Jacobs
BC
van Doorn
PA
Dutch GBS Study Group
Distinguishing acute-onset CIDP from fluctuating Guillain-Barré syndrome: a prospective study
Neurology
 , 
2010
, vol. 
74
 (pg. 
1680
-
6
)
Stephanova
DI
Daskalova
M
Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part III. Paranodal internodal demyelination
Clin Neurophys
 , 
2005a
, vol. 
116
 (pg. 
2334
-
41
)
Stephanova
DI
Daskalova
M
Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part II. Paranodal demyelination
Clin Neurophys
 , 
2005b
, vol. 
116
 (pg. 
1159
-
66
)
Sung
JY
Kuwabara
S
Kaji
R
Ogawara
K
Mori
M
Kanai
K
, et al.  . 
Threshold electrotonus in chronic inflammatory demyelinating polyneuropathy: correlation with clinical profiles
Muscle Nerve
 , 
2004
, vol. 
29
 (pg. 
28
-
37
)
Van den Bergh
PY
Hadden
RD
Bouche
P
Cornblath
DR
Hahn
A
Illa
I
, et al.  . 
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
Eur J Neurol
 , 
2010
, vol. 
17
 (pg. 
356
-
63
)
Van der Meché
FG
Van Doorn
PA
Meulstee
J
Jennekens
FC
GBS-consensus group of the Dutch Neuromuscular Research Support Centre
Diagnostic and classification criteria for the Guillain-Barré syndrome
Eur Neurol
 , 
2001
, vol. 
45
 (pg. 
133
-
9
)
Van Doorn
PA
Diagnosis, treatment and prognosis of Guillain-Barré syndrome (GBS)
Presse Med
 , 
2013
, vol. 
42
 
Pt 2
(pg. 
e193
-
201
)
Yuki
N
Hartung
HP
Guillain-Barré syndrome
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
2294
-
304
)