Abstract
Background: Studies of patients with hereditary neuropathy with liability to pressure palsies (HNPP) have shown accentuated distal slowing along with nonuniform conduction abnormalities at segments liable to compression, suggesting a distal myelinopathy as an underlying pathophysiological mechanism.
Methods: We evaluated 12 patients with HNPP by standard nerve conduction studies and by conduction to more proximal muscles in the arm and leg. Three CMT1A patients and six healthy subjects also were evaluated as controls.
Results: Median and peroneal motor nerves in all HNPP patients showed prolonged distal motor latencies (DML) (mean ± SE, 5.9 ± 0.41 and 8.63 ± 0.58 milliseconds), but the ulnar and tibial DML were minimally prolonged or normal (mean ± SE, 3.87 ± 0.16 and 5.66 ± 0.24 milliseconds). DML to forearm flexor (median and ulnar nerves) or anterior tibial muscles (peroneal nerve) were also normal.
Conclusion: Accentuated distal slowing is found primarily in median and peroneal nerve segments liable to pressure palsies or repetitive trauma. However, the ulnar and tibial nerves, which are less liable to compression, have minimal changes. In addition, distal latencies to more proximal muscles in the arm and leg do not have distal slowing. These findings do not support a distal myelinopathy as a determinant of the conduction abnormalities in HNPP.
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent sensory and motor mononeuropathies. The mononeuropathies tend to occur at sites subject to compression.1,2⇓ The disease is associated with a 1.5-megabase deletion on chromosome 17p11.2-12 bearing the peripheral myelin protein 22 (PMP22) gene.2,3⇓ PMP22 expressed in myelinating Schwann cells is reduced by 50% in patients4 and in heterozygous PMP22 knockout mice.5 Because all myelinating Schwann cells express PMP22 as part of the coordinated program of myelin gene expression,6 all myelinating Schwann cells are affected by the PMP22 deletion, both proximally and distally.
Previous electrophysiological studies have shown accentuated distal slowing with mildly reduced motor conduction velocities.7-12⇓⇓⇓⇓⇓ Because of disproportionate distal slowing, it has been suggested that there is accentuated distal myelinopathy in HNPP.7-9⇓⇓ It is unclear why distal myelinating Schwann cells should behave differently than other myelinating Schwann cells; therefore, we prospectively investigated the hypothesis of whether there is a distal myelinopathy in HNPP.
Methods.
Subjects.
Twelve patients with HNPP were prospectively evaluated. All cases had the deletion of chromosome 17p11.2-12 bearing the PMP22 gene, which was confirmed by genetic testing. No patient had diabetes or other known conditions causing neuropathy. Three CMT1A patients (with PMP22 duplication) and six healthy subjects were also evaluated as controls.
Nerve conduction study.
Motor and sensory nerve conduction studies of median, ulnar, peroneal, tibial, and sural nerves were performed using conventional methods. The distal stimulation distances for motor conduction studies were 7 centimeters in the arms and 9 centimeters in the legs. In addition, we also conducted motor nerve conduction studies to more proximal limb muscles. The median nerves were stimulated at the elbow distally and at the axilla proximally. The recording electrodes for the median nerve studies were placed over the bellies of the forearm flexor muscles, including flexor carpi radialis, flexor digitorum superficialis, and palmaris longus. The recording electrodes for the ulnar nerve studies were placed over the bellies of forearm flexor muscles, including flexor carpi ulnaris and flexor digitorum profundus. The reference electrodes were placed over the tendons at the wrist. For the peroneal nerve studies to the anterior tibial muscles, we placed the stimulating electrodes distally at the fibular head and proximally at the popliteal fossa. The recording electrodes were placed over the belly of the anterior tibial muscle. The distances were again 7 centimeters in the arms and 9 centimeters in the legs. For the median and ulnar innervated forearm muscles, we ensured that volume conduction did not contribute to the responses by stimulating both nerves and adjusting recording electrode position to keep the response specific to the nerve being studied.
Conduction block was considered to be present when the amplitude of compound muscle action potentials (CMAP) from proximal stimulation was <50% of the amplitude of CMAP from distal stimulation. Focal slowing at a compression site was considered to be present when a decrement of >10 meters/second was identified in comparison with the distal motor conduction velocity. Ten patients had the left arm and leg studied, whereas two patients had the right side evaluated.
The terminal latency index (TLI) was calculated for each motor nerve using the following formula: TLI = terminal distance (millimeters)/(distal motor latency [DML; milliseconds] × conduction velocity [meters/second]). A low TLI indicates accentuated slowing of distal segments.
Statistical analysis.
Percents and means were compared using the Student’s t-test, and differences were considered significant at p < 0.05.
Results.
Subjects.
Twelve patients (4 men and 8 women) were identified. The age range for the patients was 9 to 56 years (mean age, 41 years). The range of the onset of symptoms was 6 to 20 years, except for one asymptomatic patient aged 43 years. All symptomatic patients presented with a typical history of HNPP, such as recurrent sensory and motor deficits in those nerves liable to compression.
Electrophysiology.
Electrophysiological studies of HNPP patients showed that the conduction velocity of motor nerves was normal or only mildly reduced, with some focal slowing in sites subject to compression. In agreement with findings of previous studies, the prolongation of DML was a prominent feature for all HNPP patients.7-10⇓⇓⇓ We then compared motor nerve conduction data for different nerves (table 1). DML to distal muscles in median (92%) and peroneal (100%) nerves were more frequently abnormal than those in ulnar (67%) and tibial (25%) nerves (table 1). Mean DML ± SE for median and ulnar nerves were 5.90 ± 0.41 milliseconds (12 patients) and 3.87 ± 0.16 milliseconds (12 patients), respectively. There was a difference in DML between median and ulnar nerves (p < 0.001). A difference (p < 0.001) was also found between the mean peroneal DML ± SE (8.63 ± 0.58 milliseconds [n = 10]) and the mean tibial DML ± SE (5.66 ± 0.24 milliseconds [n = 9]) (see table 1). These differences were observed in every patient, which excludes the possibility that there was an undue effect of any outlying value.
DML in different nerves when recorded from distal muscles in HNPP
Because there is typically a 1-millisecond difference in DML between the median and ulnar nerves, even in normal subjects, we compared the DML as a percentage of the upper limit of normal. The mean DML ± SE of the median nerve was 131% ± 9% of the upper limit of normal, which was different (p = 0.03) from that of the ulnar nerve (111% ± 4%) (figure). This difference (p < 0.001) was even more prominent when the mean peroneal DML ± SE (157% ± 11%) was compared with the mean tibial DML ± SE (94% ± 4%).
Figure. Comparison of distal motor latency slowing in different nerves in hereditary neuropathy with liability to pressure palsy. *Percent of the upper limit of normal of distal motor latency. **p = 0.03. ***p < 0.001.
To further characterize the distal slowing in motor nerves, we calculated their respective TLI. These results were consistent with the findings of the DML comparisons. TLI of median and peroneal nerves were significantly different from those of ulnar and tibial nerves (see table 1). F-wave latencies and conduction velocities were normal or only mildly abnormal (table 2). Conduction block or focal slowing was most commonly observed in the ulnar nerve across the elbow (92%) but was less common in the peroneal nerve across the fibular head (40%).
Motor CV and F-wave latencies in HNPP
To determine whether prolonged DML simply represented a length-dependent myelinopathy, we assessed DML from distal segments of nerves innervating proximal muscles, such as forearm flexor and anterior tibial muscles. DML to these proximal muscles were normal in all HNPP patients (table 3). There was no significant difference in these DML between normal subjects and HNPP patients. In contrast, DML to proximal muscles were very prolonged in CMT1A patients, a true diffuse myelinopathy.12 These data suggest that the distal segments of the shorter nerves to proximal muscles are not affected in HNPP.
DML in different nerves when recorded from proximal muscles
To clarify whether distal slowing may be secondary to distal axonal degeneration, we also analyzed the amplitudes of CMAP in all motor nerves (see table 1). Reduced CMAP amplitude was found only in 1 of 12 median, 2 of 12 ulnar, and 1 of 8 tibial nerves. This does not indicate significant axonal loss in most nerves. The mean CMAP amplitude ± SE for the peroneal nerves was decreased. Eight of 12 peroneal nerves had reduced CMAP amplitudes; however, 4 of the 8 had evidence of focal slowing or conduction block at the fibular head, and 2 of the 8 were nonresponsive, for which fibular head compression could not be substantiated.
Sensory nerve conduction velocity was either slowed in the distal segments or nonresponsive. Sensory nerves were diffusely affected in HNPP patients (table 4). Distal latencies were abnormal in 83% of median nerves, 83% of ulnar nerves, and 92% of sural nerves. Absent responses were also seen (17%, 25%, and 42% of median, ulnar, and sural nerves). These results are similar to those of previous studies.8-10⇓⇓
Results of sensory nerve conduction studies for patients with HNPP
Discussion.
This study confirms that there is a unique electrophysiological pattern in HNPP. This pattern is characterized by accentuated distal slowing in some nerves, multifocal conduction slowing at the sites of entrapment, and only mildly reduced conduction velocities of other segments of motor nerves. Distal sensory conduction velocities appear to be diffusely abnormal. These findings are consistent with those of previous reports.7-11,13⇓⇓⇓⇓⇓ However, we have extended these studies to determine whether the conduction abnormalities reflected a distal myelinopathy, as suggested by previous studies, or whether the changes were due to predisposition to pressure palsies.
Although we found prolonged DML in all 12 of our patients with HNPP, the degree of slowing was not the same in all nerves. No distal slowing was seen in the tibial nerve, despite the fact that it is the longest nerve studied. The ulnar nerve always was less involved than the median nerve despite similar length. This variability in DML prolongation is similar to findings of previous reports based on mean values.13 In addition, the length of the peroneal nerve to the anterior tibial muscle, which has a normal DML, is approximately equal to that of the median nerve in the hand, which had prolonged DML. Thus, the distal motor slowing does not appear to be related to the length of the nerve. The distal slowing is also unlikely to be secondary to distal axonal loss, because most CMAP amplitudes were normal (see table 1).
DML to the proximal muscles were normal. This finding suggests that the prolonged DML of the median and peroneal nerves were specific to the distal segments to the abductor pollicis brevis and extensor digitorum brevis but not to the forearm flexor and anterior tibial muscles, which again emphasizes that not all distal segments of these nerves had slowing. Taken together, these results demonstrate that a distal myelinopathy or a simple length-dependent process cannot explain the electrophysiological findings of HNPP.
Abnormal findings of sensory nerve conduction studies for patients with HNPP are also interesting but difficult to interpret. In line with findings of previous studies,8-10⇓⇓ our results demonstrate slow distal sensory nerve conduction. Whether the changes of sensory conduction are due to pressure palsies or are related to a more generalized process is not clear. Sural sensory nerves were as involved as the median and ulnar sensory nerves, suggesting that conduction abnormalities in sensory nerves may be more diffuse processes than those in motor nerves.
The pathophysiological mechanism(s) causing HNPP is not understood. Pathologic studies of biopsied nerves from HNPP patients demonstrate diffuse “sausage-like” swellings in nerve fibers, known as tomacula.7,14,15⇓⇓ Although these pathologic findings are striking, they cannot by themselves explain clinical abnormalities in HNPP, such as accentuated distal slowing and multiple entrapments. Tomacula are diffusely present along nerves, but clinical abnormalities in HNPP are multifocal.
We believe a more likely explanation for the focal nature of clinical problems in HNPP is that the nerves are more susceptible to compression. Thus, the median nerve is more susceptible to entrapment than the ulnar nerve at the wrist, and the peroneal nerve is more susceptible than the tibial nerve at the ankle. Although only the median nerve tends to be entrapped in otherwise normal people, we postulate that the ulnar nerve at the wrist and the peroneal nerve at the ankle are potential sites of repetitive injuries in people with HNPP. However, the tibial nerve at the ankle seems to be spared from trauma or entrapment, which is consistent with what is known about tibial nerve entrapment (namely, tarsal tunnel syndrome). The entrapment is rare in otherwise normal subjects and is controversial.16
Why nerves in patients with HNPP should be particularly susceptible to compression is unknown; however, this susceptibility presumably results from the reduction of PMP22 in the myelinating Schwann cells. Understanding the function of PMP22 will be critical to discerning the pathogenesis of HNPP and other types of hereditary sensory and motor neuropathy.
Acknowledgments
Supported in part by the Charcot-Marie-Tooth Association.
- Received December 3, 2001.
- Accepted in final form March 14, 2002.
References
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