Acute motor conduction block neuropathy Another Guillain–Barré syndrome variant

Patients and methods.

Results.

Patient 1.

Electrophysiologic examination at day 7 after onset showed 1) abnormal area reduction of proximal CMAP in both ulnar nerves in the segment above elbow-below elbow with slow conduction velocity, slightly prolonged distal motor latencies (DMLs), but normal distal CMAP amplitudes (figures 1, 2⇓); 2) normal DML, distal CMAP amplitude, and conduction velocity in right median, both peroneal, and right tibial nerves but slow conduction velocity (35 m/s) and low amplitude CMAP (0.8 mV) in left tibial nerve; 3) normal minimal F wave latency of right median, right and left ulnar, and left peroneal nerves but slightly prolonged F wave of right peroneal nerve (58 ms); 4) normal distal sensory conductions and SNAP amplitudes, normal ulnar antidromic sensory conductions, and normal SNAP amplitude ratios in the below elbow-wrist and in the above-below elbow segments (see figure 2); and 5) normal median and ulnar SEPs (see figure 2). EMG of proximal and distal muscles showed reduced recruitment pattern with high frequency discharging motor units, but no spontaneous activity. Serial recordings showed that abnormal area reduction in the above-below elbow segment of the ulnar nerves gradually improved to disappear in 3 weeks without development of excessive temporal dispersion of proximal CMAPs (see figure 1). Conduction velocity in the above-below elbow segment returned in the normal range and to values comparable with conduction velocities in the below-elbow wrist segment in the 3rd to 5th week. DMLs shortened to borderline normal values in 2 weeks (see figure 1). Sensory conductions repeated at week 2 remained normal as did SNAP ratios across the sites of motor CBs and ulnar SEPs.

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Figure 1. Linear graphs showing electrophysiologic data of the nerves showing conduction blocks in the two patients. In abscissae weeks: time 0 is the first recording performed 1 week after onset in Patient 1, and 3 days after onset in Patient 2. In ordinates are (A) area reduction (in percentage) of proximal compound muscle action potential (CMAP) vs distal CMAP; (B) increased duration (in percentage) of proximal CMAP vs distal CMAP; (C) distal CMAP amplitude expressed in millivolts (mV); (D) distal motor latency (DML) expressed in milliseconds (ms); and (E) motor conduction velocity (MCV) expressed in meters/second (m/s). ○ = right median nerve; • = left median nerve; □ = right ulnar nerve; ▪ = left ulnar nerve; ⋄ = right peroneal nerve; ♦ = left peronel nerve; ▵ = right tibial nerve; ▴ = left tibial nerve. The values regarding the above elbow-below elbow segment of the ulnar nerves are shown by dashed lines.

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Figure 2. Patient 1, left ulnar nerve 7 days after onset. Motor conduction velocity (MCV) recorded from abductor digiti minimi and sensory conduction velocity (SCV) recorded antidromically from digit V after stimulation at the wrist (W), below the elbow (BE), and above the elbow (AE). The values of proximal compound muscle action potential (CMAP) area expressed as percentage of the distal CMAP and the values of proximal sensory nerve action potential (SNAP) amplitude expressed as percentage of the distal SNAP are reported above the tracings. Conduction velocities are between tracings. Somatosensory evoked potential (SEP) after stimulation at the wrist and recording at Erb point (ERB), C7, and scalp (C4) with reference to ipsilateral earlobe (A₂).

Patient 2.

Electrophysiologic examination at day 3 after onset showed 1) abnormal area reduction of proximal CMAP in all six motor nerves examined: median nerves in the elbow-wrist segment, ulnar nerves in the below elbow-wrist and in the above-below elbow segments, and peroneal nerves in the above-below fibular head segments (figures 1 and 3⇓); 2) slow conduction velocity in the below elbow-wrist segment of the left ulnar nerve and in the above-below elbow segment of both ulnar nerves (see figure 1); 3) reduced distal CMAP amplitudes in nerves of the upper limbs and slightly prolonged DMLs in the right ulnar, left median, and peroneal nerves (see figure 1); 4) absent F response in the left ulnar nerve, borderline prolonged minimal F wave latency of the left median nerve (32 ms), and normal minimal F wave latency of the right ulnar and both peroneal nerves; 5) normal distal sensory conductions and SNAP amplitudes and normal antidromic sensory conductions and SNAP amplitude ratios across the sites of CB; and 6) normal SEP from stimulation of the median and ulnar nerves. EMG showed reduced recruitment pattern with high frequency discharging motor units, but no spontaneous activity. Serial recordings showed that abnormal area reduction of proximal CMAPs in intermediate segments improved to disappear in 2 to 5 weeks without excessive temporal dispersion, and motor conduction velocities and DMLs returned to normal values (see figures 1 and 3⇓). Distal median and ulnar CMAP amplitudes improved (at least twice the baseline value) without increased duration and temporal dispersion (see figures 1 and 3⇓). Sensory conductions and SNAP ratios across the sites of motor CBs remained normal during the study period. Spontaneous activity was never recorded on EMG.

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Figure 3. Patient 2, right ulnar nerve 3, 10, and 38 days after onset. Motor conduction velocity recorded from abductor digiti minimi after stimulation at the wrist (W), below the elbow (BE), and above the elbow (AE). The value of distal compound muscle action potential (CMAP) amplitudes expressed in millivolts (mV) and the values of the proximal CMAP area (expressed as percentage of the distal CMAP) are reported above the tracings.

Discussion.

The patients we report had an acute motor neuropathy with early abnormal area reduction of CMAPs in intermediate and distal nerve segments but no clinical and electrophysiologic evidence of sensory involvement. Serial electrophysiologic studies demonstrated that abnormal area reduction of CMAPs was the result of partial CB.

Recently four similar patients have been described.6-9⇓⇓⇓ Because some clinical, electrophysiologic, and laboratory findings matched the features of multifocal motor neuropathy (MMN),10 the term “acute multifocal motor neuropathy” has been proposed.6,8⇓ However, five motor GBS patients with CBs in forearm nerve segments and spared sensory potentials even across the segments with motor blocks have also been reported.11 We will discuss some features of these patients, which, in our opinion, allow us to delineate a distinct GBS variant.

Three of four reported patients with acute motor neuropathy with CB had a preceding C. jejuni enteritis, and two had elevated anti-GM1 along with anti-GalNAc-GD1a antibodies in one.6,8⇓ C. jejuni is considered the most common infective antecedent in patients with GBS. Japanese patients with GBS subsequent to Campylobacter enteritis frequently have antibodies to GM1 or other gangliosides, and molecular mimicry between gangliosides and lipopolysaccharide of C. jejuni isolated from patients with GBS has been demonstrated.12 C. jejuni infection with anti-GM1 antibodies occurs more frequently in patients with pure motor GBS in Europe.13 Our patients had a preceding enteritis and high titers of antibodies to GM1 and GD1a along with anti-GD1b antibodies in one patient. A recent C. jejuni infection could be demonstrated in one patient. Although these findings suggest the association of acute motor neuropathy with CBs with antecedent C. jejuni infection and specific antiganglioside antibodies, this association, as for other GBS types, is far from being the rule.

In Western countries, motor-sensory GBS is considered the most frequent clinical variety (approximately 75% of cases).1 Although a sensory deficit may be difficult to demonstrate early in the disease, 61% of patients have low amplitude or absent sensory potentials in the upper extremities during the first week and up to 80% of patients have electrophysiologic evidence of sensory nerve involvement in at least one nerve during the disease.14,15⇓ Sensory neurography has been mostly limited to distal nerve segments and probably underestimates the extent of sensory involvement in patients with GBS. As a matter of fact, SEPs, performed early during the disease course, demonstrated proximal conduction slowing, whereas distal sensory conductions were commonly normal in a high percentage of patients.16 In two large European series, 9.5% and 16% of patients had pure motor GBS, and the vast majority showed axonal features.17,18⇓ Overall, patients with an acute exclusively motor neuropathy and CBs, as the ones we describe, seem to be uncommon in Western countries.

Areflexia is one of the two clinical features required for GBS diagnosis.19 Deep tendon reflexes may be preserved throughout the disease course in patients with acute motor axonal neuropathy (AMAN) and have been considered indicators of rapid clinical recovery.20,21⇓ Moreover, 48% of Chinese and 33% of Japanese patients with AMAN showed hyperreflexia in the recovery phase.22,23⇓ In Europe, patients with pure motor GBS had preserved tendon reflexes up to MRC grade 3 paresis,11 and more recently an AMAN patient with hyperreflexia has been reported.24 One of our patients had hyperreflexia, and the other had normal reflexes throughout the disease course. Both had an MRC grade 3 to 4 weakness with electrophysiologically demonstrated sparing of sensory fibers. Brain and spinal MRI excluded concomitant corticospinal pathway involvement in one patient. Moderate weakness and normal afferent branch of the reflex arch could account in AMAN patients and in our patients for the relative preservation or earlier reappearance of myotatic reflexes, but they do not explain hyperreflexia. Recently, electrophysiologic evidence of lower motor neuron hyperexcitability has been reported in some patients with AMAN.23 In conclusion, preserved reflexes and even hyperreflexia may occur in patients with pure motor GBS and are not inconsistent with the diagnosis. We believe that the diagnostic criterion of areflexia should therefore be applied only to the sensory-motor forms of GBS.

It has been suggested that the most common sites of nerve involvement in patients with GBS are not randomly distributed throughout the nerve. The distal motor nerves, the proximal segments, and the sites prone to compression are most vulnerable.3,25,26⇓⇓ Early in the disease, electrophysiologic abnormalities are often mild or nonspecific.14,19⇓ Motor CB has been documented in only 2 to 15% of patients with GBS within 3 weeks from disease onset, and CB in intermediate nerve segments in the first days of the disease, such as in our patients, is uncommon.3,14,27⇓⇓ In our patients, as in three previously reported,6-8⇓⇓ CBs were found at the above-below elbow segment of the ulnar nerves. It is possible that mechanical impairment of the blood-nerve barrier at this common entrapment site may render this nerve segment more vulnerable to immunologic attack.3,25,26⇓⇓

Detection of CB along sensory fibers is difficult because of a more marked effect of the distance-related temporal dispersion in SNAP compared with CMAP.28,29⇓ In patients with chronic acquired demyelinating neuropathy, the proximal/distal amplitude ratio of CMAPs was reduced in 76% of nerves compared with only 21% of SNAPs, and an abnormal decline of proximal/distal amplitude ratio of SNAP occurred at the same sites of motor CB in only 16% of nerves.29 These findings raise the issue as to whether sensory fibers are less vulnerable to demyelination (because of a greater safety factor of nerve transmission) or is it simply more difficult to demonstrate demyelination in the sensory system (because of the greater effect of temporal dispersion).29,30⇓ Nonetheless, the absence of sensory CB and conduction slowing across the segments that showed focal motor CB and the normality of distal sensory conductions and SEPs well demonstrate, in our patients, a true dissociation of the pathophysiologic process between motor and sensory fibers (see figure 2).

The pathologic basis of CB is thought to be acute demyelination. Experimental studies of synchronously demyelinating lesions showed that recovery from CB is characterized by dyssynchronization and increased duration of CMAP caused by temporal dispersion and slowing of conduction velocity, indicative of remyelination.31,32⇓ In the nerves of our patients, CB disappeared in a few weeks without excessive temporal dispersion of proximal CMAP (see figures 1 and 3⇑), suggesting a pathophysiologic mechanism different from demyelination.

An acute, exclusively motor, axonal neuropathy often associated with anti-GM1 and anti-GD1a IgG antibodies and a preceding C. jejuni infection has been recognized in northern China and in other countries.22,33-35⇓⇓⇓ AMAN has been associated with extensive axonal loss and poor outcome, but some patients recover more promptly than expected.22,35⇓ Autopsy studies of AMAN showed neuropathologic changes ranging from minimal pathology to severe Wallerian-like degeneration and deposits of immunoglobulin, complement, and macrophages at the nodes of Ranvier.36,37⇓ It has been suggested that reversible conduction failure and axonal degeneration constitute the pathophysiologic mechanisms in IgG anti-GM1–positive patients with AMAN.26,38⇓ Anti-GM1 antibodies have been shown to block conduction and suppress sodium channel currents in some, but not all, experimental studies.39-41⇓⇓ The aforementioned observations suggest that anti-GM1 antibodies bind to the axolemma at the Ranvier node and may induce reversible physiologic conduction failure or axonal degeneration, possibly depending on the intensity of local immune reaction, or to complement deposition. Our patients may represent an “arrested” AMAN, possibly because of early treatment. However, it is debatable whether they should be classified as having AMAN just because the immune-mediated attack probably occurs on the axolemma, inducing physiologic conduction failure but not axonal degeneration. The term AMAN, as commonly used, conveys the idea of axonal degeneration, and we do not believe it is useful to group patients with different pathophysiology and prognosis under the same denomination.

Because of sensory sparing, preserved tendon reflexes, presence of motor CBs in forearm segments, and anti-GM1 antibodies, the neuropathy we describe has been considered an acute type of MMN.6,8⇓ In our opinion, the term “multifocal” implies not only the presence of CBs but also clinical asymmetry, which was not present in our patients. As discussed previously, retained reflexes or hyperreflexia does not exclude the diagnosis of a GBS variant. Moreover, anti-GM1 antibodies described in MMN are IgM, whereas the antibody isotype is IgG in our cases and in those with other GBS variants.42

All considered, we believe it is more appropriate to classify this neuropathy as a GBS variant, which we suggest calling “acute motor conduction block neuropathy,” emphasizing the presence of CBs and avoiding the pathophysiologic implication that all CBs are demyelinating in nature. We would like to stress that for patients with GBS, sequential electrophysiologic studies are important to elucidate the primary mechanism at the basis of weakness among demyelination, physiologic conduction failure, and Wallerian degeneration. This helps to properly classify patients and establish prognosis.