Abstract
Article abstract-Clinical, electrodiagnostic, and pathologic studies indicate that the Guillain-Barre syndromes (GBSs) include both primary demyelinating and primary axonal forms. The axonal forms are usually thought to have a poorer prognosis, with less chance for rapid or complete recovery. In northern China, epidemics of one axonal form, acute motor axonal neuropathy (AMAN), occur annually in the summer. Autopsy studies in some fatal cases have demonstrated wallerian-like degeneration of motor roots and motor fibers in the peripheral nerves. Recovery of such patients would require axonal regeneration along the entire length of the nerve fiber. In a 2-year prospective study of GBS at a single hospital in northern China, 42 patients were classified as having either AMAN (32 patients), acute inflammatory demyelinating polyneuropathy (AIDP) (8 patients), or as undetermined (2 patients) by electrodiagnostic criteria. Their recoveries were monitored clinically. The recovery times of AMAN and AIDP patients were similar: the median time to regain the ability to walk 5 meters with assistance was 31 days for patients classified as having AMAN and 32 days for those classified as having AIDP. These rapid recovery times are incompatible with severe wallerian degeneration of the ventral roots and motor nerve fibers. The rapid recoveries observed in AMAN patients could be explained by relatively quickly reversible immune-mediated changes at nodes of Ranvier in motor fibers, by degeneration and regeneration of intramuscular motor nerve terminals, or both.
NEUROLOGY 1997;48: 695-700
The Guillain-Barre syndromes (GBSs) are characterized clinically by acute flaccid paralysis, areflexia, and albumino-cytologic dissociation. [1] Based on electrophysiology and pathology, GBSs can be divided into either predominantly demyelinating or predominantly axonal patterns. Feasby et al. [2,3] identified a severe axonal type of GBS, acute motor-sensory axonal neuropathy (AMSAN), with poor prognosis for recovery, and demonstrated severe wallerian-like degeneration in peripheral nerves at autopsy. Electrophysiologically, AMSAN cases are characterized by absent or low compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAP), without evidence of demyelination. This pattern has been thought to be due to an immune-mediated injury to axons leading to wallerian-like degeneration. [2-4] Recovery in this setting would require axonal regeneration. Because axonal regeneration rarely exceeds 1 mm/day in adults, recovery would thus necessarily be slow and incomplete.
Recently, a more restricted axonal pattern of GBS, termed "acute motor axonal neuropathy" (AMAN), has been described. [4-10] AMAN is characterized by low CMAP amplitudes and normal SNAP amplitudes without evidence of demyelination. AMAN occurs in summer epidemics in northern China. [5-7] In our initial studies, we noted that some AMAN patients in China recovered quickly and were ambulatory at 1-year follow-up. [5,6] In this 2-year prospective study, we followed all GBS patients admitted to the Second Teaching Hospital (STH) and determined the rate of recovery in AMAN and acute inflammatory demyelinating polyneuropathy (AIDP) patients. On the basis of these results, we propose possible mechanisms to explain the rapid recovery of AMAN patients.
Methods.
The study population included all patients with clinically defined GBS admitted to STH of Hebei Medical College in Shijiazhuang, People's Republic of China, a general hospital serving all ages, between January 1, 1993, and December 31, 1994. To be included, patients had to have neurologic symptoms for less than 30 days. Serial motor and sensory conduction studies were performed with a Dantec Cantata machine (Skoulunde, Denmark) by standard methods. The diagnostic criteria for AIDP and AMAN were based on motor nerve conduction studies as described previously [7] (Table 1). Patients whose initial nerve conduction studies showed absent motor evoked responses were classified as inexcitable. While in the hospital, each patient had upper and lower limb motor strength assessed daily according to the MRC scale and the Hughes clinical scale (grade 5, assisted respiration required; grade 4, bed-bound; grade 3, able to walk 5 meters with a walker or support; grade 2, able to ambulate 5 meters independently; grade 1, minor signs and symptoms) by trained observers who were blinded to the electrophysiologic subtype of the patients' diagnoses. All patients received similar treatment, including fresh plasma and intrathecal methylprednisolone. None received intravenous human immune globulin (IVIg) or plasmapheresis. Recoveries were analyzed by using Kaplan-Meier survival curves. Patients lost to follow-up were excluded after their last follow-up dates.
Table 1. Classification criteria
Results.
During the 2-year study period, 42 patients fulfilled the entry criteria and were enrolled in the study. The AMAN pattern was found in 32 patients (76%) and the AIDP pattern in 8 (19%). Two patients had inexcitable nerves at presentation. Age (Figure 1) and seasonal (Figure 2) distributions were comparable to those in our previous reports. [5-7] The AMAN form clearly had seasonal (June to September) and pediatric predominances. The clinical features of the patients are summarized in Table 2. The median follow-up time was 33 days (range, 7 to 120 days). Nine patients (21%) were discharged prior to reaching Hughes grade 3. The median time for improvement of one Hughes grade was 27 days for AMAN patients and 34 days for AIDP patients. The median times for patients with peak Hughes grades of 4 and 5 to reach grade 3 was 31 days for AMAN patients and 32 days for AIDP patients (Figure 3; the distribution of peak Hughes grades is shown in the table set within the figure). The median times for patients with peak arm weakness worse than MRC grade 4 to reach grade 4 was 30 days for AMAN patients and 38 days for AIDP patients (Figure 4). The median time for patients with peak leg weakness worse than MRC grade 3 to reach grade 3 was 26 days for AMAN patients and 27 days for AIDP patients (Figure 5). No significant differences in the rates of recovery for AMAN and AIDP patients were found.
Figure 1. Age distribution.
Figure 2. Seasonal distribution.
Table 2. Clinical features
Figure 3. Probability of reaching Hughes grade 3. Inset: Peak clinical grade distribution.
Figure 4. Probability of reaching MRC grade 4 in the upper limbs. Inset: Peak upper-limb weakness distribution.
Figure 5. Probability of reaching MRC grade 3 in the lower limbs. Inset: Peak lower-limb weakness distribution.
Illustrative clinical histories of AMAN patients with rapid recovery.
Patient 1.
A 9-year-old girl from a rural village presented to STH with acute flaccid paralysis. There was no history of prodromal illness. At presentation, she had bilateral seventh nerve palsies. Motor exam showed MRC 1 in the arms and paralysis in the legs. She was areflexic, but had a normal sensory examination. She first recovered some movement in her legs on day 14 of her illness, and by day 25 she was able to walk with assistance. Electrodiagnostic findings from day 11 are shown in Table 3 and her pattern of recovery in Figure 6.
Table 3. Nerve conduction studies of patient 1
Figure 6. Recovery of patient 1.
Patient 2.
A 2-year-old girl from a rural village presented to STH with acute flaccid paralysis. She had had bloody diarrhea 12 days before onset of weakness. At presentation, she had arm weakness (MRC 3) and leg paralysis. Her CSF on day 6 of illness showed 4 cells/mL and 0.85 g/L of protein. She was first able to move her legs again on day 27 of illness. By day 38, she was able to walk with assistance. Nerve conduction studies from day 9 are shown in Table 4 and her pattern of recovery is shown in Figure 7.
Table 4. Nerve conduction studies of patient 2
Figure 7. Recovery of patient 2.
Discussion.
In these patients, the AMAN form of GBS had a rate of recovery comparable to that of the AIDP form. Although the number of AIDP patients in this study is small, their rates of recovery are comparable to those in the North American GBS Study [11] and the Dutch GBS Trial, [12] in which a large majority of patients presumably had AIDP. The median times for the untreated groups in the North American trial to improve one clinical grade were 40 days, and 41 days in the Dutch trial for the group given plasmapheresis. Our study had a high proportion of predominantly pediatric patients, which probably accounts for the somewhat more rapid recovery of both AMAN patients (27 days) and AIDP patients (34 days), since previous studies have shown that the rate of recovery is age-related. [13]
Although a few patients experienced prolonged recoveries, most improved quickly. This observed rapid rate of recovery in AMAN is incompatible with wallerian-like degeneration of a large proportion of motor fibers in the ventral roots, as described in some autopsied cases. [2-4,8] For this reason, severe axonal degeneration extending as proximally as the ventral roots is probably not the underlying pathology in most of the AMAN patients who recover rapidly.
Several possible pathophysiologic mechanisms could account for the quick recovery and absent or low-amplitude CMAPs without generalized features of peripheral nervous system (PNS) demyelination: (1) a myopathic process; (2) disruption of neuromuscular transmission; (3) distal demyelination; (4) physiologic failure of conduction along motor axons without irreversible structural damage; (5) wallerian-like degeneration restricted to the distal motor nerve twigs. The first two mechanisms have been ruled out by electrophysiologic or morphologic observation, or both. Any or all of the last three mechanisms explain the rapid rate and extent of paralysis and the rapid recovery seen in AMAN.
Distal demyelination.
We think this mechanism is unlikely. First, with serial nerve conduction studies, we have not observed any features of PNS demyelination, including prolongation of distal motor latency. Second, the recovery of distal motor evoked amplitude in most cases has been gradual and lags behind clinical recovery, suggesting regeneration of distal axons rather than distal demyelination alone. However, one cannot completely exclude a process of primarily distal demyelination with secondary distal axonal degeneration. Third, the target of immunologic attack appears to be the adaxonal region, as discussed below. [10]
Physiologic impairment of conduction.
This hypothesis is supported by several lines of evidence. First, autopsy studies of some AMAN patients with severe paralysis show minimal pathologic change in the motor roots and nerves. [8,9] On teased fiber preparations, some fibers show mild lengthening of the nodes of Ranvier. [9] Immunoglobulin and complement are frequently localized at the nodes of motor fibers by immunocytochemistry. [10] Macrophages migrate to these nodes and appose or surround the nodal axon. [9,10] In many instances, they dissect into the internodal periaxonal space. [8,9] Each of these steps could potentially disrupt conduction through nodes of Ranvier and explain the observed electrophysiologic changes. Furthermore, anti-GM1 antibodies have also been shown to block conduction [14,15] and have recently been reported to affect both sodium and potassium channels in voltage-clamped single fibers. [16] Anti-GM1 antibodies are commonly present in the sera of AMAN patients. [7,17,18]
Motor nerve terminal degeneration.
The rapid recovery of AMAN patients might also be explained by axonal degeneration and rapid regeneration of the terminal and immediate preterminal segments of motor axons. If only a small length of nerve fiber were damaged, recovery would only necessitate regeneration of the axon through a short distance. In an AMAN patient with rapid recovery, a motor point biopsy showed extensive wallerian-like degeneration of myelinated axons in the intramuscular nerves and loss of innervation at the neuromuscular junction (see companion paper for details). [19] Early denervation potentials were a common finding in many AMAN patients (unpublished observations; C.Y. Gao, manuscript in preparation). If denervation was secondary to wallerian degeneration at the level of the spinal root, then denervation potentials would be delayed for up to 2 weeks [20] and recovery would be prolonged and incomplete. Therefore, both the early appearance of denervation potentials and the early recovery suggest a distal motor nerve lesion, and not wallerian-like degeneration starting proximally. [20]
The last two processes are not mutually exclusive. A spectrum of pathologic severity, ranging from minor nodal changes and associated complement deposition at nodes of Ranvier to severe wallerian degeneration of motor nerve fibers, has been observed in Chinese AMAN autopsy cases. [8] An attractive hypothesis is that the primary immune attack is directed against the nodes of Ranvier. [9,10] Antibodies directed against specific glycoconjugates of bacterial lipopolysaccharides could bind to similar epitopes at motor nodes of Ranvier. [21,22] Binding of complement-fixing antibodies might lead to local complement activation and attraction of macrophages. [10] The lack of a blood-nerve barrier in the motor nerve terminals and roots may make these areas particularly accessible to antibody and thus a favored target site. Thus, a spectrum of severity could result. In severe cases, such as the AMSAN cases described by Feasby et al., [2,3] extensive wallerian degeneration beginning in the spinal roots prevents rapid recovery. In contrast, we suggest that in most AMAN patients only physiologic effects on the nodes or axonal degeneration restricted to the motor nerve terminals, or both, allow a rapid recovery.
- Copyright 1997 by Advanstar Communications Inc.
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