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Effects of Spontaneous Chronic Hypoglycemia on Central and Peripheral Nervous System in Insulinoma Patients before and after Surgery: A Neurophysiological Follow-Up

Clinical Institute of Nervous and Mental Diseases (G.P., E.V., C.D., G.S., F.P.) and Medical Clinic II (Endocrinology) (F.L., M.F., G.T.), La Sapienza University, Rome; Istituto di Ricovero e Cura a Carattere Scientifico Mediterranean Neurological Institute (G.P., C.D., G.S.), Pozzilli (Isernia), Italy

Address all correspondence and requests for reprints to: G. Pozzessere, M.D., Via Monteciccardo 11, int. 66, 00138 Rome, Italy.

	Abstract

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To investigate the effects of spontaneous chronic hypoglycemia on the peripheral and central nervous system, a multimodal neurophysiological evaluation [median somatosensory (mSEP), brain stem auditory (BAEP), and visual (VEP) evoked potentials recordings] was performed in seven insulinoma patients before and 3 and 6 months after surgical removal of tumor.

Before surgery, mSEP findings showed abnormal reduction in peripheral wrist-Erb conduction velocity in three patients as well as a pathological increase in Erb-N13, N13-N20, and Erb-N20 conduction times in five cases. BAEP and VEP recordings gave pathological results in two patients. Moreover, during hypoglycemia, the III-V and I-V interpeak latencies of BAEPs were significantly prolonged (P < 0.01 and P < 0.005, respectively) compared to recordings in euglycemia.

After 6 months, a mSEP recovery, even if partial was noted in four patients, BAEPs were normalized in one case, and VEPs were unmodified. Compared to presurgery data, these recordings showed a significant (P < 0.05), but incomplete, shortening of BAEPs (III-V and I-V interpeak latencies) and mSEPs (Erb-N13 and Erb-N20 conduction times).

Our findings demonstrate that multiple and selective neurophysiological abnormalities are present in insulinoma patients, confirm that hypoglycemia impairs suddenly brain stem function, and show that after tumor removal, long recovery times for improvement of some neurophysiological anomalies are requested.

	Introduction

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IT IS WELL known that hypoglycemia depresses cerebral energy metabolism. Thus, it is likely to cause a temporary impairment of cerebral functions and, less frequently, can produce permanent brain damage and death (1, 2). Cortical and hippocampal atrophy and ventricular enlargement may occur (3); sometimes diffuse demyelinization has been observed (3).

At the peripheral level, insulin-induced hypoglycemia has been shown to produce acute axonal degeneration in both nondiabetic and diabetic animals (4) and to alter the anterograde fast components of axonal transport in rats (5). Furthermore, a distal symmetrical predominantly motor neuropathy is a rare syndrome that can occur in patients with hypoglycemia secondary to insulinoma (6, 7, 8, 9).

During the past few years, a number of studies have examined the effects of hypoglycemia on central nervous system functions, and neurophysiological as well as neuropsychological changes have been noted (10, 11, 12, 13, 14). However, the extent and mechanisms of nervous system impairment during hypoglycemia have not yet been fully described.

The electrophysiological techniques potentially offer objective means of assessing peripheral and central nervous system function (15). Moreover, the recording of electrical events occurring along the somatosensory, auditory, and visual pathways constitutes a noninvasive diagnostic tool in the detection of even subclinical nervous system impairments.

To our knowledge, peripheral along with central nervous system function in patients suffering from spontaneous hypoglycemia due to insulinoma has not yet been investigated by means of multimodal neurophysiological evaluation.

The aims of our study were to investigate, by means of multimodal evoked potentials recordings, 1) the effects of spontaneous chronic hypoglycemia, due to an insulin-secreting tumor, on the peripheral and central nervous system; and 2) the reversibility or progression of the neurophysiological changes upon subsequent surgical removal of tumor.

	Subjects and Methods

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Seven patients (five men and two women; aged 16–61 yr; mean ± SD, 33.4 ± 15.2) with a 7- to 36-month (mean ± SD, 18.1 ± 9.9) history of recurrent hypoglycemic reactions were studied. Their clinical data are reported in Table 1.

All patients underwent neurological examination, electromyography of upper and lower limbs, and psychometric tests.

A multimodal electrophysiological evaluation [median somatosensory (mSEP), brain stem auditory (BAEP), and visual (VEP) evoked potentials] was performed, before surgery, under both euglycemic (E) and hypoglycemic (H) conditions. At the first session, plasma glucose concentrations were maintained in the normal range (4.4–5.0 mmol/L) by means of a variable glucose infusion. At the second session, the glucose infusion was stopped early in the morning of the study, thus allowing glycemic levels to decrease. When plasma glucose levels reached 2.4 mmol/L, evoked potentials were recorded. In addition, all patients underwent an electrophysiological follow-up 3 and 6 months after surgical removal of insulinomas, which were confirmed by biopsy. After surgery, the glycemic levels returned steadily to the normal range.

Visual acuity, fundus oculi and audiometric exam were normal in each subject.

mSEP recordings were performed with an electrical stimulus (a square wave of 0.1 ms duration, 7 Hz frequency) with surface electrodes on the median nerve at the wrist. The bioelectrical signal was recorded by electrodes placed 1) in the medio-claveal area (Erb), 2) in the cervical area (C7), and 3) on the scalp in relation to the specific somatosensory receiving area (C'3 or C'4, 2 cm posterior to C3 or C4) contralateral and ipsilateral to the stimulated limb. A noncephalic reference was used (contralateral shoulder to the stimulated limb). A ground electrode was placed on the ipsilateral arm to the stimulated limb, which was maintained at 36 C by means of a thermistor-infrared lamp system.

BAEP recordings were performed with an acoustic stimulus in the form of clicks (unfiltered square waves of 0.120 ms duration with alternating polarity and a frequency of 10 Hz). Monaural stimulation at an intensity of 80 decibels hearing level was achieved, while a masking white noise (at an intensity of 60 decibels hearing level) was transmitted to the ear contralateral to the stimulated ear. The active electrode was placed at the vertex, the reference electrode was placed on the mastoid ipsilateral to the stimulated ear, and the ground was placed contralateral.

VEP recordings were obtained with a checkerboard pattern reversal on a television monitor, subtending an angle of 17°. The spatial checkerboard frequency was 0.78 cycles/degree, and the temporal frequency of pattern reversal was 2 Hz. The mean luminance was 60 candela/m², and the contrast between dark and bright checks was 50%. The active electrode was placed 5 cm above the inion along the midline, the reference electrode was at Fz, and a ground electrode was placed on the mastoid.

Further details regarding these techniques have been previously reported (16).

Analysis of recordings

The following parameters were taken into consideration: mSEP: wrist-Erb conduction velocity (CV; representative of CV along the peripheral nerve fibers from the wrist to the brachial plexus), interval between Erb-N13 [the conduction time (CT) across the brachial plexus and the cervical cord], N13-N20 interval (the CT from the cervical cord/lower brain stem lemniscal pathways to the cortex), and Erb-N20 transit time (the CT from the brachial plexus to the cortex) (17, 18); BAEP: interpeak latency (IPL) values of waves I–III (CT from the acoustic nerve to the pons), III–V IPL (central CT from the pons to the midbrain), and I–V IPL (expression of the activity of the auditory pathways from the periphery to the midbrain) (19, 20); and VEP: the latency of the positive wave with the highest voltage (P100, which represents the response of the visual cortex to retinal stimulation) (21, 22).

Evoked potentials were considered pathological if the peak latency (VEP: P100) and interpeak intervals (BAEP: I–III, III–V, and I–V IPLs; mSEP: Erb-N13, N13-N20, and Erb-N20 CTs) were more than 3 SD above the mean values of 20 age- and sex-matched control subjects. In addition, the CV (mSEP: wrist-Erb CV) was considered pathological if it was 3 SD less than the normal average (23).

Statistical analysis

All electrophysiological data were statistically analyzed by means of ANOVA with repeated measures and Student’s t test for dependent samples to compare measures obtained under both euglycemic and hypoglycemic conditions. The same statistical analysis were performed during the entire follow-up employing euglycemic data recordings. This procedure allowed each subject to serve as his/her own control, and the results are presented as the mean ± SE. In addition, Pearson’s r correlation was used to evaluate the statistical relationship between electrophysiological findings and age of patients, illness duration, number of the severe hypoglycemic episodes, and fasting glycemia. P < 0.05 was considered statistically significant.

	Results

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Upon admission, neurological examination and electromyography were normal, except in subject 3, who showed bilateral muscle atrophy of the thenar eminence with electromyographic signs of denervation, fibrillation, and sharp waves discharges. Psychometric tests were normal in all subjects.

mSEP recordings

Before surgery, under both euglycemic (E) and hypoglycemic (H) conditions, in five insulinoma patients (no. 1, 3, 4, 6, and 7) mSEP data were pathological in at least one parameter (see Table 2). In particular, peripheral wrist-Erb CV was reduced in cases 1, 4, and 6, bilaterally; Erb-N13 CT was pathologically increased in subjects 3 and 4 bilaterally, as in cases 1 and 6 it was impaired only after left arm stimulations; N13-N20 CT was only increased in subject 6 after left arm stimulation; and Erb-N20 CT was prolonged in subjects 3 and 6 for the left stimulation and in subject 7 for the right one. During hypoglycemia no change was statistically significant at any level compared to those during euglycemia (Table 3).

Concerning statistical analysis of mSEP data, Erb-N13 [before surgery, 5.26 ± 0.12 ms (±SE); at 3 months, 5.17 ± 0.12 ms; at 6 months, 5.04 ± 0.10 ms] and Erb-N20 (before, 11.47 ± 0.18 ms; at 3 months: 11.33 ± 0.19 ms; at 6 months, 11.17 ± 0.18 ms) CTs were significantly reduced at 6 months compared to those recorded before surgery (P < 0.05; Fig. 1). Moreover, the Erb-N20 CT observed at 6 months was significantly reduced compared to that at 3 months of follow-up (P < 0.05).

View larger version (20K): [in this window] [in a new window]   Figure 1. Multimodal neurophysiological (mSEP, BAEP, and VEP) follow-up in insulinoma patients before (a) and 3 (b) and 6 (c) months after surgical removal. Data are expressed as the mean ± SE.

BAEP recordings

Before surgery, pathological results were obtained only in patient 5 relative to III–V and I–V IPLs bilaterally in both euglycemia and hypoglycemia (Table 2). Statistical evaluation revealed a significant lengthening in BAEPs for III–V (P < 0.01) and I–V (P < 0.005) IPLs during hypoglycemia compared to those during euglycemia (Table 3). Three months after surgery no differences emerged. After 6 months, BAEP measurements were normalized in III–V (bilaterally) and I–V IPLs (after the right stimulation), whereas the I–V IPL after the left one was still pathological (Table 2). Moreover, a significant (P < 0.05) reduction of III-V (before, 2.02 ± 0.04 ms; at 3 months, 1.97 ± 0.05 ms; at 6 months, 1.94 ± 0.03 ms) and I–V (before, 4.20 ± 0.05 ms; at 3 months, 4.17 ± 0.05 ms; at 6 months, 4.13 ± 0.04 ms) IPLs was observed compared to those during euglycemia before surgery (Fig. 1). On the contrary, I–III IPL data were not significantly modified (before, 2.18 ± 0.03 ms; at 3 months, 2.20 ± 0.02 ms; at 6 months, 2.19 ± 0.02 ms).

VEP recordings

Data for P100 wave latency were abnormal only in patient 4, showing an increase in latency in both stimulated eyes during euglycemia and hypoglycemia before surgical treatment (Table 2).

The statistical comparison between euglycemia and hypoglycemia of VEP measurements did not show any significant difference (Table 3). During the follow-up 3 and 6 months after surgery, VEP parameters were still pathological in subject 4. No relevant data emerged from the statistical analysis, although a modest P100 wave shortening was observed (before, 109.7 ± 1.6 ms; at 3 months, 109.3 ± 1.8 ms; at 6 months, 108.8 ± 1.5 ms; Fig. 1).

Overall analysis

Before surgery, all insulinoma patients except one showed abnormalities of at least one of the measured parameters under both euglycemic and hypoglycemic conditions compared to those in the control group. After surgical removal of tumor, the neurophysiological recordings at 3 months produced unmodified data, whereas the SEP and BAEP recordings at 6 months resulted in the following normalized data: wrist-Erb CV in two of three patients, Erb-N13 CT in two of four patients, and Erb-N20 CT in two of three patients for SEP recordings, and III–V (bilaterally) and I–V (upon right stimulation) IPLs in the only patient who showed previous abnormalities. VEPs were unchanged even after 6 months of follow-up.

No clear correlation between electrophysiological findings and age of patients, illness duration, number of hypoglycemic episodes, and fasting glycemia was found under either hypoglycemia or euglycemia conditions during the entire follow-up.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Neurophysiological changes have been previously described for the condition of induced hypoglycemia in both normal subjects and insulin-dependent diabetic patients (13, 14, 24, 25). In this study, evoked potential recordings, which provide useful information regarding nervous system function, have shown a wide spectrum of abnormalities during the course of spontaneous chronic hypoglycemia in humans.

It has been reported (14) that in man, experimentally induced hypoglycemia during both acute and moderately prolonged (for 1 h) conditions does not impair the peripheral CV from wrist to brachial plexus. Vice versa, our SEP findings showed evidence of peripheral CV involvement, even if clinically silent, in three of insulinoma patients. Perhaps, peripheral nerve impairment requires longer manifestation of a condition of hypoglycemia similar to that encountered in patients with insulin-secreting tumor. In fact, in this condition, both clinically symmetric polyneuropathy (7, 9) and a reduction of motor conduction velocity (6, 8) have been described.

The Erb-N13 CT was bilaterally affected in an insulinoma patient (no. 3) with bilateral muscle atrophy of the thenar eminence. Both of these findings suggest spinal cord involvement. In subjects 1, 4, and 6, the Erb-N13 CT was altered without any clinical evidence of muscle atrophy, indicating subclinical spinal cord impairment. In one patient, a pathological N13-N20 CT value (case 6) was also observed, revealing damage to the central somatosensory pathways during chronic hypoglycemia.

The central nervous system involvement during hypoglycemia is confirmed by the significant abnormal increases in BAEP III–V and I–V IPLs, suggestive of anatomical-functional damage to the brain stem structures (26, 27). Also recently it has been observed by means of BAEP recordings that mild hypoglycemia causes a brain stem dysfunction in both nondiabetic and diabetic rats (28) and in healthy men (24). It is noteworthy that wave V is thought to be generated in midbrain structures, including the inferior colliculus, and that this is the neural center with the highest rate of glucose consumption in rats (27). Therefore, if the same is true in humans, wave V may be especially susceptible to reduction of glucose supply. Our data indicate that hypoglycemia in insulinoma patients can also selectively and precociously impair brain stem centers (26, 27).

In normal subjects, VEP latency appears less modified by low blood glucose (13). Conversely, during spontaneous chronic hypoglycemia there is also an impairment of the optic pathways, as shown by the pathological increase in P100 latency in case 4. However, given the complexity of the phenomena involved in the genesis of this potential, it is not possible to identify the lesion site.

It is worth noting that neurophysiological deteriorations existing in the hypoglycemic condition are not modified when glycemic levels were normalized in insulinoma patients. Furthermore, 3 months after tumor removal, our data indicate no significant modifications with respect to the previous controls. These observations suggest that a return to an euglycemic state is not immediately followed by a regression of the electrophysiological alterations.

Only after 6 months we did observe a significant, but not always complete, recovery of the neurophysiological parameters. In fact, the electrophysiological responses obtained with the three methods were not contemporaneously ameliorated in the same patients; thus, a broad and patchy map of the neurophysiological recovery induced by the restoration of the metabolic control was found. At 6 months, a significant improvement was revealed in peripheral-central CTs in somatosensory pathways (from the brachial plexus to the cervical cord: Erb-N13 CT; from the brachial plexus to the cortex: Erb-N20 CT), as well as in brain stem auditory tracts (from the pons to the midbrain: III–V IPL; from the periphery to the midbrain: I–V IPL). Concerning the peripheral CV of mSEP (wrist-Erb) and the latency of the P100 wave of VEP, amelioration was obtained by means of surgical removal of tumor even if this was not significant. Therefore, the normalization of metabolic control seems to permit a selective neurophysiological restoration, which is evident in some insulinoma patients after a follow-up of at least 6 months and is quicker at the peripheral-central level than at the peripheral level.

Glycopenia can be the major injurious factor to certain nervous cell populations (29, 30, 31), presumably by accentuating a preexisting underlying susceptibility (11, 32). The lack of a clear correlation between electrophysiological data and illness duration, intensity of hypoglycemic episodes, or number of episodes of severe hypoglycemia confirms the complexity of the mechanisms leading to abnormal evoked responses. Under these conditions, recurrent hypoglycemia could produce relatively permanent impairment of nervous system function over time in insulinoma patients. Then, the long recovery times requested for the improvement of the neurophysiological anomalies after tumor removal would represent a recovery, even anatomical, of the involved structures, which could regenerate or, in any case, restabilize themselves after serious functional damage.

	Acknowledgments

 
We thank Mrs. G. Spinelli for editorial assistance.

Received July 9, 1996.

Revised December 20, 1996.

Accepted February 4, 1997.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pozzessere, G. Articles by Tamburrano, G. Search for Related Content PubMed PubMed Citation Articles by Pozzessere, G. Articles by Tamburrano, G.