Unrecognized Charcot-Marie-Tooth Disease

Abstract

Charcot-Marie-Tooth disease (CMTD), Type 1, is a peripheral neuropathy characterized by a slowly progressive weakness and muscle atrophy, first affecting the feet and legs and much later the hands and forearms [1]. From a neurophysiologic point of view, a prolonged latency of evoked responses should be expected both on proximal and distal muscles as a consequence of the diffuse myelinopathy, which is the primary defect in this disease [2]; a further increase in the latency, as well as a decrease in the amplitude of responses, should be expected in distal muscles when their innervation is altered by the secondary axonopathy [3] of the longest nerve fibers [1]. As a general rule, reinnervation phenomena, which typically are accompanied by an increased sensitivity to muscle relaxants [4-9], are much more frequent if the axonal damage occurs in a young patient [10]. Case Report A 48-kg, 17-yr-old girl was scheduled for surgical removal of a cavernous angioma of the right frontal lobe. Since the age of 12 yr, the patient received chronic treatment with barbesaclone for epilepsy. The rest of her history was unremarkable. On admission, she appeared to be well. Neurologic examination was normal, with the exception of "diminished tendon reflexes and a mild equinovarus deformity of the feet." Premedication was with barbesaclone, diazepam, and atropine. Induction of anesthesia was performed with fentanyl (0.05 mg), droperidol (2.5 mg) and thiopenthal (300 mg) intravenously. Maintenance of anesthesia was with N2 O (60%), oxygen (40%), and isoflurane (1%-1.5%). Vecuronium (5 mg) was given intravenously to facilitate tracheal intubation. During the uneventful surgical procedure, the endtidal partial pressure of CO2 was maintained at 30-35 mm Hg. A simultaneous monitoring of neuromuscular (NM) transmission on the distal muscles of both legs was attempted 40 min after administering vecuronium. Our purpose was to ascertain whether the "diminished tendon reflexes" and the chronic treatment with barbesaclone (an unusual anticonvulsant) could result in alterations of the patient's sensitivity to vecuronium. Moreover, since the neurosurgical procedure was supposed to cause a transient motor deficit in the left leg, we decided to compare the recovery from NM blockade (NMB) in the right and left flexor hallucis brevis (FHB) muscles. Two Datex Relaxograph (DR) NMT monitors were used. Surface electrodes were placed as indicated by Sopher et al. [11]. With intervals of 20 s, train-of-four stimuli were delivered to the right and left posterior tibial nerves at the ankle with a frequency of 2 Hz and an intensity of 70 mA. Muscular responses were not detected by the instruments or by visual inspection. Hypersensitivity to vecuronium was suspected, and it was decided to monitor the subsequent recovery from NMB by the use of the "uncalibrated mode." This is a means by which the assessment of transmission is restricted to the train-of-four ratio (T1 being the 100% reference value for T4 in each train). It must be noted that the electromyographic (EMG) response "window" of the DR is between 3 and 18 ms, starting from the stimulation time point; it follows that muscular responses whose distal latency is greater than 18 ms cannot be recorded by the instrument. Monitoring was started 60 min after induction of anesthesia Figure 1. A nerve stimulator was used 17 and 33 min later on the right and left tibial nerves, respectively, at the ankle to evaluate the effects of a tetanic stimulation at 50 Hz for 5 s. Posttetanic facilitation was not obtained.Figure 1: Simultaneous assessment of recovery from curarization on the right and left flexor hallucis muscles by the use of the Datex Relaxograph NMT monitor in the "uncalibrated mode." Monitoring was started 60 min after the administration of vecuronium (0.1 mg/kg) and was continued for 90 min (with five interruptions at times indicated at the top of the figure). TET = tetanic stimulations at 50 Hz for 5 s delivered to the right posterior tibial nerve at the end of the first interruption and, respectively, to the left tibial nerve at the end of the second interruption; 1 = administration of 5 mg of edrophonium. (See text for details.)Visible responses in the form of small and irregular movements of plantar flexion of the foot were noted on both sides a few minutes after the tetanic stimulation of the left tibial nerve (approximately 100 min after vecuronium). Being unaccompanied by EMG activity, these responses were interpreted as indicating that a recovery from NMB was occurring in some flexor muscles, but not yet in the FHB. Edrophonium (5 mg) did not elicit any EMG activity. At the end of the operation, just before discontinuing isoflurane, EMG responses were still absent, whereas movements of plantar flexion were much more regular and evident than before. Due to the potential for requiring postoperative ventilatory support, the patient was transferred to the intensive care unit. On arrival, the patient was fully awake and cooperative. She was able to breath spontaneously and to move her limbs without apparent difficulties. No electrophysiologic investigations were performed. The tracheal tube was removed, and the postoperative course was quite uneventful. On the second postoperative day, the patient and her mother were evaluated according to a clinical, genetic, and electrophysiologic protocol [12]. A diagnosis of CMTD, Type 1, was made. Motor conduction studies are shown in Table 1: no evoked EMG responses were recorded by surface electrodes on the left FHB, while responses recorded on the right FHB had very small amplitude (0.05 mV) and a very long distal latency (25.1 ms). Needle electrodes revealed moderate signs of denervation and reinnervation in the anterior tibial muscles.Table 1: Motor ConductionDiscussion It is well known by neurologists that in many affected patients, CMTD remains undiagnosed [13]; this is because, in spite of the foot deformities, and in spite of the pathologic findings revealed by neurophysiologic investigations, the patient's disability may be surprisingly slight, or even absent [1,13]. Being unaware of this, and having omitted the basal assessment of NM transmission prior to administering the vecuronium, we did not recognize that the evoked responses of the FHB were too delayed to be recorded by the DR, nor did we suspect that their amplitude could be so small, as shown 2 days later by neurologists. Signs of neuropathy were so mild that we confined their importance to the possible occurrence of a reduced safety margin of NM transmission. Hypersensitivity to vecuronium was our first hypothesis. Later, other possibilities, such as errors in drug administration, pharmacologic interference with barbesaclone, and even the occurrence of neuroapraxic phenomena, were erroneously considered as additional or alternative explanations for the "abnormal" recovery from NMB. As shown in Table 1, postoperative investigations revealed that our difficulties could have been prevented, at least in part, if NMB had been monitored on intrinsic muscles of the hand (the latency of their responses was not outside the window of DR). We cannot say whether these muscles were hypersensitive to vecuronium, nor can we say whether the loss of functioning motor units and the probable presence of reinnervation phenomena rendered hypersensitive to vecuronium the FHB. To our knowledge, there are no reports to confirm this assumption, but the late appearance and the progressive increment of visible responses during the second part of our monitoring suggest that hypersensitivity to vecuronium was probably present, both in the FHB and in other intrinsic muscles of the feet. It is widely accepted, mainly based on retrospective reviews, that the use of muscle relaxants is uneventful in patients with CMTD [14-16]. This is probably because, in the vast majority of these patients, when denervation phenomena occur they are restricted to the distal segments of lower and upper limbs. Having low clinical importance, any residual NMB in these segments is likely to be underestimated at the end of operation and immediately thereafter. It should be noted, on the other hand, that hypersensitivity is well recognized in the rare instances in which denervation is more extended and affects respiratory muscles [17].