Three Modality Evoked Potentials in Charcot-Marie-Tooth Disease (HMSN-l) Natan Gadoth, MD, Carlos R Gordon, MD, DSc, Naomi Bleich, MSc

and HUel Pratt, PhD

Sixteen patients with dominant hereditary motor-sensory neuropathy type I (HMSN I), members of 5 families, under­went trimodality evoked potential studies. All patients had clinically normal optic nerves. History of deafness was present in 3 patients and sensory-neural hearing defect was found in 5 of 7 patients in whom audiometry was obtained. In 43.7 percent of the subjects significant prolongation of P 100 of the YEP was found. Prolongation of N 19 of the SEP was found in all 12 subjects examined. Significant bilateral prolongation of peak I of the ABEP was found in 37.5 per­cent of the subjects and in 50 percent of the ears examined: these findings indicated that in addition to penpheral nerves, the myelin of the optic and cochlear nerves is also affected in HMSN type L Key words: Evoked potentials, hereditary motor-sensory neuropathy, Otarcot-Marie-Tooth, auditory, deafness.

Gadoth N, Gordon CR, Bleich N, Pratt H. Three modality evoked potentials in Charcot-Marie-Tooth disease (HMSN-1).

The association of Charcot-Marie-Tooth disease (CMTD) with clinical optic atrophy was reported soon after its original description and since then in a significant number of publications.

As a number of these reports describing the association of CMTD and optic atrophy lack electrodiagnotic studies, one may claim that not every case had CMTD. Neverthe­less, fully proven cases of such an association do exist [1-3] .

Some claim that this association is indeed the co-occur­rence of CMTD and Leber's optic atrophy in the same individual [4].

Since Dyck and Lambert's reclassification of the hereditary neuropathies in 1968 [5,6], the term CMTD was replaced by the better defmed group of HMSN I. Based on this classification, Smith studied 15 autopsies and found only one case with unilateral optic atrophy, confirming the view that both conditions only appear rarely concomitantly [7]. HMSN types I and II were very

From the Department of Neurology, Beilinson Medical Center, Petah Tiqva and Tel Aviv University Sackler School of Medicine (NG, CRG); and Evoked Potentials Laboratory, Technion, Israel Institute of Technology (NB, HP), Haifa.

Received for publication: December 3, 1990. Accepted for publication: March 3, 1991.

Correspondence address: Prof. Natan Gadoth, Department of Neurology, Beilinson Medical Center, Petah Tiqva 49 100, Israel.

Brain Dev 1991;13:91-4

rarely associated with neural deafness [8-10]. These observations point to the possibility of cranial

nerve involvement in HMSN. Indeed, the introduction of modern neurophysiological methods resulted in the docu­mentation of central vestibular dysfunction [11] and abnormalities in the visual [12-15], somatosensory [14-16] and auditory brain stem [17,18] evoked potentials (VEP, SEP, ABEP, respectively).

It is surprising that there are no reports of tri-modality evoked responses (VEP, SEP and ABEP) recorded in a group of patients with HMSN I.

In a preliminary study we have found abnormal YEP in a significant number of patients with HMSN I [19]. In the present report we summarize the results of YEP, SEP and ABEP studies in a larger newly diagnosed group of patients. In familial disorders such as HMSN I, screen­ing may disclose affected children who are considered normal by their parents and quite often by their pediatri­cians. There is no way in which one can study families with HMSN I omitting the adult cases. Thus, any new ob­servation may be of interest to neurologists as well as to neuropediatricians.

PATIENTS AND METHODS

Patients Sixteen patients with HMSN I were included in the study.

Nine of the 16 patients were females. The mean age was 33.6 ± 19.5 (range 6-78 years). The patients belonged to five families. In each patient the dominant mode of in heritance was confirmed by clinical examination of at least another affected family member.

History of visual and/or hearing impairment was look­ed for and a routine pure tone and speech audiometry was obtained in 7 of the patients using a Maico M-24-1 audio­meter.

Evoked potential

Visual evoked potentials (VEPs)

VEPs were recorded over 0 1 , O2 and Oz referenced to Fz and elicited by pattern reversal stimulation. The stimulus source was a television checkerboard screen with 32 checks (each check substending 17 minutes of arch) which reversed at the rate of 2/sec. The system band pass was 2-30 Hz and the gain 200 k. Two averages of 128 trials were obtained with monocular full-field stimulation of each eye. Silver disc electrodes were used and electrode impedance was always below 5 kD.

Auditory brainstem evoked potentials (ABEPs) ABEPs were recorded between vertex and the mastoid process, ipsilateral to the stimulated ear, while the contra­lateral mastoid served as the ground. Each ear was stimu­lated in tum through magnetically shielded earphones by transducing pulses of 0.1 msec duration to clicks at 115 db peak equivalent SPL. The rate of stimulation was 10/ sec. 2,048 responses were averaged to produce each trace and a duplicate of each average was made to assess repro­ducibility. The band pass was 100-2,000 Hz at a gain 0[200 k.

EVOKED POTENTIALS

NORMAL SUBJECT

LT

® 108

!~ V.E.P

e ~~L msec

e~Jl3.95.9 t A.B.E.P ~

® o.5~vl

2~

HMSN-1 PATIENT

LT

n __ ~M I~V ~

r~ ~ S.E.P l 18.1 medi8nnerve e 1~1 ~

~ Fig 1 Evoked potentials (left side stimulation) from a normal subject and from a patient with HMSN I (patient no 2).

92 Brain & Development, Vol 13, No 2, 1991

Somatosensory evoked potentials (SEPs)

SEPs were recorded from electrodes on the contra-lateral scalp (C3 /C4) and a midfrontal (Fz) reference point. The median nerve on each side, in turn, was stimulated via silver surface electrodes placed at the wrists. The stimulus was a rectangular electric pulse of 0.1 msec duration presented at a rate of 4/sec. The intensity of the stimulus was increased gradually until a visible twitch of the thenar was elicited and then a supramaximal stimulus intensity was used throughout the test. The recording band passs was 30-1,500 Hz and the gain 200 k. Two averages of 512 stimuli were obtained for each stimulated side.

Latencies or interpeak latency differences that were beyond ± 2.0 SD from the normative age-matched mean obtained in our laboratory were considered abnormal.

RESULTS

Evoked potentials from a normal subject and from one of the patients are shown in Fig 1.

Clinical and electrophysiological data are shown in Table 1. Diagnosis was confirmed in each family by the presence of the classical clinical features of HMSN I and

Table I Clinical and electrophysiological data in patients with HMSN-1 disease

VEP(P100) ABEP SEP (19) Normal Normal Normal Normal values values values values

Pa· Age/ (msec) (msec) (msec) (msec)

tient sex! Peak I Peak V-no family peak I

105± 1.65 ± 4.0 ± 19.28 ± 4.0 0.16 0.24 2.10

Rt Lt Rt Lt Rt Lt Rt Lt

1 70/F/A 114+ 118+ 2.4+ 2.0+ 4.2 4.2 33.5+ 0.0+

2 30/M/A 118+ 124+ 2.1+ 2.2+ 4.0 4.1 26.0+ 26.0+

3 32/F/A 110 102 2.0+ 1.8 3.8 3.8 29.0+ 29.0+

4 36/F/A 100 100 1.8 1.8 3.8 3.8 0.0+ 0.0+

5 34/F/A 102 102 1.4 1.4 4.2 4.2 42.0+ 44.8+

6 14/F/A 100 100 1.7 1.7 4.0 4.0 0.0+ 0.0+ 7 12/M/A 114+ 114+ 1.7 1.7 4.0 4.0 37.6+ 37.6+

8 6/M/A 106 106 1.6 1.6 4.0 4.0 ND ND

9 50/F/B 118+ 124+ 2.0+ 2.0+ 4.3 4.3 ND ND

10 30/F/B 108 114+ 2.0+ 1.7 4.4 4.4 ND ND

11 22/F/B 106 104 1.7 1.6 4.1 4.0 ND ND

12 18/M/C 108 108 2.1+ 2.1+ 4.2 4.2 26.4+ 24.4+

13 43/M/C 100 102 2.0+ 2.1+ 4.1 4.0 0.0+ 0.0+

14 29/M/D 110 124+ 1.6 2.2+ 3.8 4.1 0.0+ 26.0+

15 34/F/D 100 104 2.2+ 2.2+ 4.2 4.2 28.5+ 0.0+

16 78/M/E 120+ 108 2.4+ 1.8 3.9 4.4 32.0+ 32.0+

+: abnormal values, 0.0: no potential detected, ND: not done.

typical nerve conduction velocity fmdings in one or more affected members of each family. All four patients young­er than 18 years had defmite signs of HMSN I. In three families the diagnosis was supported by sural nerve biopsy showing typical numerous "onion bulbs." History of hearing impairment was present in three patients and pure sensory-neural hearing loss was documented in 5 of the 7 patients who underwent audiometry. All patients with abnormal audiometry had abnormal ABEP. However, in 2 patients with unilateral ABEP abnormality the audiogram was normal. Clinical evaluation of optic nerve functions including visual acuity, confrontation visual field examina­tion and fundoscopy were normal in all patients. A signi­ficant prolongation of P100 was present in the VEP obtained from 7 patients (43.7%). In 4 patients both eyes were affected while in 3 the PlOO was abnormal on one side only. ABEP showed a significant prolongation of peak I in 10 patients and in 50 percent of the ears examin­ed. In 6 patients (37.5%) both ears were affected while in 4, peak I was prolonged on one side only. The value for peak V- peak I latency was normal in all 16 patients. In 12 patients the median nerve stimulation SEP was per­formed. Three patients lacked responses from both sides while in 3 others a response could not be obtained from one side only and in 9 a clear N19 peak was identified, at least to one side, with impressive prolongation of its latency.

DISCUSSION

Our fmdings of prolonged P100 in 43.7 percent of the examined patients is in agreement with previous reports claiming that VEP is abnormal in a significant number of patients with HMSN. This percentage of abnormality is similar to the 33.3 percent found by Carrol et al [15] among 15 such patients.

N19 latency was prolonged in all of the patients in whom SEP was obtained. ConSidering the marked pro­longed peripheral conduction time present in our patients, as usually expected in HMSN I, the prolonged Nt 9 is mainly or entirely due to peripheral defect. Jones et al [16] and Halliday et al [14] have calculated sensory central conduction time in CMTD and found it to be prolonged in approximately one-third of their patients. However, more than half of the patients were considered to be clinically "atypical."

Of special interest were the ABEP findings. There was a significant bilateral prolongation of peak I in 6/16 patients (37.5%) and a unilateral abnormality in 4/16 (25%). Thus, peak I was prolonged in 16 of 32 recorded ears (50%). The integrity of the auditory pa~hway in the brainstem was indicated by the normal V-I interval in all the patients examined. Possible conductive hearing loss could also cause prolongation of peak I latency. However, in the patients in whom abnormal audiometry

was obtained, it was always of the sensory-neural type. It seems from the above that the cochlear nerve function is impaired in a Significant number of patients with HNSN I. Indeed, the abnormal audiometric findings, indicating sensory-neural hearing loss obtained in 5 out of 7 patients and history of hearing impairment in 3, is in agreement with such an assumption. Previously, Garg et al [18] reported prolongation of the latency of wave I and interpeak latency of I-III in three patients with HMSN I examined. Similar abnormalities were reported in 2 brothers with HMSN II, suggesting auditory nerve and spiral ganglia impairment [17]. Recently, Raglan et al [10] reported hearing loss in 5 of 12 patients with HMSN type I. A detailed assessment of auditory function sug­gested that the hearing loss was the result of VIII nerve dysfunction.

Although abnormalities in EP have been reported in HMSN I with a similar frequency to our fmdings, the present study is unique in showing abnormalities of all 3 modalities in a relatively large group of patients.

In five patients all trimodalities examined were ab­normal, however this finding was not related to severity of disease nor to a specific family. It is not surprising that cranial nerve dysfunction is not demonstrated in every patient. Partly, methods might be still not sensitive enough or as in other dominant conditions, incomplete penetrance might be responsible for the variable clinical and electrophysiological fmdings in the same disease.

It is conceivable that HMSN I is a chronic demyelinat­ing neuropathy involving mainly the peripheral nerves but not sparing the cranial nerves. More sophisticated neurophysiological techniques may be applied in the future to establish if any other cranial nerves are also affected.

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