Abstract
Background: In Guillain–Barré syndrome (GBS), anti-ganglioside antibodies are strongly associated with the acute motor axonal neuropathy (AMAN) form, but there are also cases of the demyelinating form of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) with anti-ganglioside antibodies.
Objective: To elucidate the patterns and sequential changes in electrodiagnostic abnormalities of anti-ganglioside-positive GBS.
Methods: Detailed serial electrodiagnostic findings were reviewed for 51 patients with GBS. Anti-ganglioside antibodies were measured by ELISA.
Results: Antibodies to GM1, GM1b, GD1a, or GalNAc-GD1a were present in 25 patients. Of these, 12 (48%) showed the AMAN pattern, 5 (20%) the AIDP pattern, and 3 (12%) isolated F-wave absence in the first examination. All five patients with the AIDP pattern showed prolonged distal latencies, but three eventually showed the AMAN pattern or rapid normalization. The remaining two still had similarly prolonged distal latencies in weeks 4 to 6, but the serial changes were distinct from those in the anti-ganglioside-negative AIDP patients who showed progressive increases in distal latencies over 2 months after onset.
Conclusions: Besides the simple axonal degeneration pattern, patients with anti-ganglioside-positive Guillain–Barré syndrome can show transient conduction slowing/block in the distal or proximal nerve segments, mimicking demyelination, but anti-ganglioside antibodies do not appear to be associated with acute inflammatory demyelinating polyneuropathy.
Clinical, electrophysiologic, and pathologic studies indicate that Guillain–Barré syndrome (GBS) includes primary axonal and demyelinating forms: acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP).1–4 The frequency of the GBS subtypes varies among countries: AMAN has been found in only 7% of patients with GBS studied in England,5 3% in a multicenter study of 11 Western countries,6 and 65% in northern China.4 In Western countries, GBS is usually caused by AIDP, and the patterns and sequential changes of the nerve conduction abnormalities in AIDP have been well described.6–8 In contrast, little is known about the serial electrodiagnostic abnormalities in patients with axonal GBS.
Previous studies have shown that anti-ganglioside antibodies are frequently found in the sera from patients with AMAN; in particular, IgG antibodies to the gangliosides GM1, GM1b, GD1a, and GalNAc-GD1a may play an important role in the pathophysiology of AMAN.9–17 However, the relationship between anti-ganglioside antibodies and neurophysiology is still debated. In northern China, positive anti-GM1 antibody serology was found for 10 (48%) of 21 AMAN patients and for 4 (33%) of 12 AIDP patients.4 Our previous study showed that 4 (12%) of 34 anti-GM1-positive patients were diagnosed with AIDP.15 These results raise the possibility that anti-ganglioside antibodies are associated with both AMAN and AIDP. In addition, AMAN was originally characterized by axonal degeneration of the motor fibers, showing simple reduction of the compound muscle action potentials (CMAPs), but some patients with the electrodiagnosis of AMAN have shown rapid clinical improvement accompanied by restoration of the distal CMAP amplitude, suggesting a conduction block in the distal nerve segments.10,18 Therefore, the electrophysiologic classification during the early phase of the illness can change in a considerable number of AMAN patients.15
To elucidate the patterns of nerve conduction abnormalities in the early phase and their sequential changes in anti-ganglioside-positive GBS, we reviewed serial electrodiagnostic studies and compared the results with those of anti-ganglioside-negative typical AIDP.
Methods.
Patients.
This study included 51 patients with GBS who underwent the first electrodiagnostic studies performed within 14 days of onset and participated in two or more follow-up studies within the first 6 weeks of onset. All fulfilled the clinical criteria for GBS.19 The patients' disabilities were evaluated on the Hughes functional grading scale.20
Electrophysiology.
Nerve conduction studies were done with a Nicolet Viking IV EMG machine (Nicolet Biomedical Japan, Tokyo) on the day of admission and sequentially for up to 6 months after onset. Motor nerve conduction studies were made of the median, ulnar, tibial, and peroneal nerves, including F-wave analyses, and anti-dromic sensory conduction studies were performed in the median, ulnar, and sural nerves. The patients were classified as having the AMAN or AIDP pattern based on the electrodiagnostic criteria of the motor nerve conduction study results.4
When patients had one of the following findings in two or more nerves during the first 2 weeks of illness, they were classified as having AIDP: 1) conduction velocity <90% of lower limit of normal if amplitude is >50% of the lower limit of normal, <85% if amplitude is < 50% of lower limit of normal; or 2) distal latency >110% of upper limit of normal if amplitude is normal, >120% of upper limit of normal if the amplitude is less than lower limit of normal; or 3) evidence of unequivocal temporal dispersion; or 4) F-response latency >120% of normal. When patients had no evidence of demyelination as defined for AIDP and had decrease in CMAP to <80% of lower limit of normal in two or more nerves, patients were classified as having AMAN. Isolated F-wave absence was defined as the F-wave persistency <20% with normal peripheral nerve conduction.14 When the nerve conduction parameters did not meet the criteria for AIDP and AMAN but were outside the normal range, the patients were classified as having “minor abnormalities.” Acute motor sensory axonal neuropathy (AMSAN) was defined as the presence of AMAN pattern in motor nerve studies and an amplitude reduction <50% of the normal limits of the sensory nerve action potentials (SNAPs) in two or more nerves.21 Normal control data were obtained from 101 healthy subjects. For distal latency, CMAP duration, conduction velocity, and F-wave latency, we defined a value outside 2.5 SD from the mean as abnormal. For the CMAP or SNAP amplitude, we defined abnormality as present if the amplitude fell below 2.5 SD of the mean of the logarithmically transformed amplitudes of the controls.10,15
Anti-ganglioside antibody testing.
The serum samples were tested for the presence of IgG antibodies to GM1, GM1b, GD1a, and GalNAc-GD1a by ELISA, as described elsewhere.22 The antibody titer (1:X) was the highest serum dilution at which the optical density at 492 nm was ≥0.1. Serum was considered positive when the titer was ≥1:500. The antibodies measured have been reported to be closely associated with the AMAN electrodiagnosis.15,17
Statistical analysis.
Differences in proportions were tested with the χ2 or Fisher exact test and differences in medians with the Mann–Whitney U test. p < 0.05 was considered significant.
Results.
Clinical profiles.
Twenty-five patients had IgG antibodies to GM1, GM1b, GD1a, or GalNAc-GD1a. Table 1 compares the clinical profiles of patients with and without these antibodies. Anti-ganglioside-positive patients more frequently had preceding gastroenteritis and less frequently upper respiratory tract infections. There were no significant differences in the disabilities between the two groups at the peak of illness. The anti-ganglioside-positive patients had less frequent facial palsy and sensory symptoms. In the anti-ganglioside-positive group, sensory symptoms were found in 10 of 25 (40%). However, 9 of the 10 had mild paresthesia/pins-and-needles in the distal limbs, and only the remaining 1 patient showed a decrease in sensations. Seventy-three percent of the anti-ganglioside-negative patients had sensory symptoms, and most of them showed decreases in vibratory, touch, or pain sensation dominantly in the distal limbs.
Table 1 Clinical features of patients with Guillain–Barré syndrome
Anti-ganglioside antibodies and electrodiagnostic findings.
Table 2 shows the electrodiagnostic findings in the first and follow-up studies done in weeks 3 to 6 in the patients with anti-ganglioside antibodies and those without them. In the first studies, there were significantly higher percentages of patients in the anti-ganglioside-positive group who showed the AMAN pattern compared with the anti-ganglioside-negative group, but there were no significant differences in the frequency of AIDP between the two groups. Three (12%) anti-ganglioside-positive patients had F-wave absence as an isolated nerve conduction abnormality. None had a conduction block (>20% reduction of CMAP amplitude between the stimulation at the wrist and elbow of the median or ulnar nerves). In the follow-up studies done in weeks 3 to 6, the percentage of AMAN patients increased in the anti-ganglioside-positive group, and the AIDP pattern increased in the anti-ganglioside-negative group. Five of the 25 anti-ganglioside-positive patients and 10 of the 26 anti-ganglioside-negative patients showed minor abnormalities in the first studies. These patients had less severe disability; the mean Hughes grade was 2.6 in the ganglioside-positive group and 3.1 in the ganglioside-negative group. These patients were considered to have milder disease in each subgroup of GBS.
Table 2 Initial and final electrodiagnostic findings in patients with Guillain–Barré syndrome
Sequential electrodiagnosis in patients with anti-ganglioside antibodies.
Sequential electrodiagnosis of the 25 patients with anti-ganglioside antibodies are summarized in table E-1 on the Neurology Web site at to www.neurology.org. In the first studies done in week 1 or 2, 12 (48%; nos. 1 to 12) patients were diagnosed as having an AMAN pattern: Almost all of these patients still had the AMAN pattern in weeks 3 to 4, whereas Patients 11 and 12 showed rapid increases in distal CMAP amplitude, though the value did not reach the normal range. Three patients (nos. 13, 14, and 21) showed F-wave absence as an isolated abnormality in the first studies, whereas two (nos. 13 and 14) developed AMAN several days later. The remaining patient (no. 21) experienced restoration of F waves associated with rapid clinical recovery, and nerve conduction studies were normal in week 4.
Five (20%) patients (nos. 16 to 20) showed the AIDP pattern in the initial studies. In all of them, the diagnosis of AIDP was based on prolonged distal latencies in two or more nerves. Two of these (nos.16 and 17) were rediagnosed as having AMAN 1 or 2 weeks later, because the distal latencies rapidly became normal. One patient (no. 18) showed rapid normalization of both the distal latencies and the CMAP amplitudes, and nerve conduction was near normal at week 3.
The electrodiagnostic findings in the anti-ganglioside-positive patients, therefore, were divided into three patterns: the AMAN pattern (simple reduction of CMAP amplitude), the AIDP pattern (prolonged distal latency), and the isolated absence of F waves with normal peripheral conduction. Figure 1 shows representative CMAP waveforms of the three patterns in the anti-ganglioside-positive patients. Sequential analysis showed that almost all of the anti-ganglioside antibody–positive patients eventually showed the AMAN pattern or normal/minor abnormalities.
Figure 1. Compound muscle action potentials (CMAPs) recorded from the abductor pollicis brevis muscle after median nerve stimulation at the wrist and elbow in patients with IgG anti-ganglioside antibodies (5 milliseconds, 2 mV/division). (A) Patient 4 showed simple reduction of the CMAP amplitudes (the acute motor axonal neuropathy [AMAN] pattern) on days 5 and 22 (see table E-1). (B) Patient 16 showed prolonged distal latency with normal CMAP on day 6. Note rapid shortening of distal latency and the decrease in distal CMAP amplitude on day 13. (C) Patient 13 showed normal CMAP amplitudes with the absence of F waves on day 4 and the AMAN pattern on day 11.
To investigate the time course of electrodiagnostic abnormalities, we compared the sequential findings in the median distal latencies from weeks 1 through 6 in five anti-ganglioside-positive patients and -negative patients with the AIDP pattern in the first study (figure 2). Anti-ganglioside-positive patients showed normalization or mildly prolonged distal latencies for the next 5 weeks, in contrast to the anti-ganglioside-negative AIDP patients, who showed a progressive increase up to around week 5.
Figure 2. Serial findings of distal latencies after median nerve stimulation at the wrist in the initial electrodiagnosis of acute inflammatory demyelinating polyneuropathy in individual patients with (A) and without (B) anti-ganglioside antibodies. Dotted line indicates the cut-off value of the criteria for demyelination.
Figure 3 compares the sequential changes in the electrophysiologic parameters in the median nerve studies between the anti-ganglioside-positive and -negative groups. The mean distal latency, CMAP duration, motor nerve conduction velocity, and F-wave latency were distinct between the two patient groups, resulting from slowing of nerve conduction in the anti-ganglioside-negative group. There were progressive increases in the distal latency and F-wave latency up to month 2 in the anti-ganglioside-negative group.
Figure 3. Serial findings of motor distal latency (A), duration of compound muscle action potential (CMAP) (B), motor nerve conduction velocity (C), CMAP amplitudes (D), F-wave latency (E), and sensory nerve action potential (SNAP) amplitude (F) in median nerve conduction studies in IgG anti-ganglioside-positive (filled circles) and -negative (open circles) patients. The data are given as means ± SEM.
Sensory nerve conduction and electrodiagnosis.
The mean amplitude of the SNAP was clearly different throughout the course, reflecting pure motor involvement in most of the anti-ganglioside-positive group (see figure 3). Abnormalities of sensory nerve conduction were found for 3 of 25 (12%) of the anti-ganglioside-positive patients. These included only slightly decreased SNAP amplitudes, disproportional to markedly reduced CMAP amplitudes, and did not meet the criteria for AMSAN. On the other hand, 18 of 26 (69%) of the anti-ganglioside-negative patients showed sensory conduction abnormalities, and 14 of 18 showed markedly decreased or absent SNAPs in two or more nerves. All the 14 AIDP patients without anti-ganglioside antibodies showed sensory conduction abnormalities, and therefore there was no case of pure motor AIDP. Association of sensory nerve conduction abnormalities and final electrodiagnosis is summarized in table 3.
Table 3 Sensory nerve conduction abnormalities and final electrodiagnosis in patients with Guillain–Barré patients
Discussion.
Our results show that there are several patterns of early electrodiagnostic abnormalities in patients with anti-ganglioside antibodies. In the initial studies, 48% of patients showed the AMAN pattern, 20% the AIDP pattern, and 12% an isolated F-wave absence. Whereas the simple AMAN pattern was most frequently found as expected, some anti-ganglioside-positive patients showed distal nerve conduction slowing or the isolated absence of F waves. In sequential studies, the electrodiagnosis was rarely changed in patients initially diagnosed as having AMAN, but those with the AIDP pattern, or “F-wave absence,” frequently showed different patterns of electrodiagnostic findings, and therefore their electrodiagnoses changed. Almost all of the anti-ganglioside-positive patients eventually had AMAN or normal/minimal abnormalities in week 4. In the early phase of the disease, some anti-ganglioside-positive patients showed conduction slowing/block in the distal or proximal nerve segments but later developed axonal degeneration or showed rapid normalization of their conduction abnormalities. These findings suggest that patients with anti-ganglioside antibodies do not appear to have typical AIDP.
In contrast, most of anti-ganglioside-negative patients showed the AIDP pattern or minor abnormalities and rarely had their electrodiagnosis changed in the follow-up studies. Moreover, the time course of nerve conduction abnormalities was very similar to that of AIDP reported in previous studies.7 Anti-ganglioside-negative patients were therefore likely to have typical AIDP. AIDP can be accompanied by secondary axonal degeneration, but in the anti-ganglioside-negative patients, transformation from the AIDP pattern to the AMAN pattern was not observed in this study.
All anti-ganglioside-positive patients with the AIDP pattern showed prolonged distal latencies, but the extent of abnormality was milder than in the anti-ganglioside-negative patients. Rapid resolution of the distal conduction slowing was found in some patients; persistent prolongation for weeks, without progressive increases, was observed in others. The time course was distinct from that of the anti-ganglioside-negative patients (see figure 2). The mechanisms of the transient or persistent prolongation of distal latency in the anti-ganglioside-positive patients are unclear. However, a number of factors other than demyelination can cause slowing of nerve conduction, such as loss of the fastest fibers, altered resting membrane potential (hyperpolarization or depolarization), and sodium channel inactivation.23
The blood–nerve barrier is anatomically deficient in the distal nerve terminals and nerve roots.24 Therefore, anti-ganglioside antibodies would preferentially access those regions. The transient distal latency prolongation and F-wave absence found in our anti-ganglioside-positive patients may be explained by reversible conduction failure in the distal nerve terminals or nerve roots. Recent reports described patients with anti-ganglioside antibodies, who showed multifocal conduction block in the forearm segments of median or ulnar nerve,25,26 but this type probably represents a rare variant and was not found in this study.
According to the electrodiagnostic criteria for AIDP and AMAN,4 electrodiagnosis is based on motor nerve conduction studies “done during the first 2 weeks of illness,” but our results showed that the electrodiagnosis of a considerable number of patients with anti-ganglioside antibodies changed during the first 4 weeks, and even within the first 2 weeks. In this regard, the electrophysiologic classification of GBS would be better determined based on sequential findings rather than only on the results of an initial study, and sequential findings up to weeks 3 to 6 appear to be important to make the final electrodiagnosis.
References
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