1164
diagnosis with primary hyperparathyroidism occurring by chance in a woman with anticonvulsant osteomalacia, but some may agree with us that this tertiary, with the adenoma the consequence of the anticonvulsant therapy. We have reported two other patients with both epilepsy and case
also
was
but did not then anticonvulsant that the consider therapy might be the cause. A new finding has come from the assays not available to earlier workers; plasma 25-H.C.C. levels were low in both our patients, thus independently confirming the presence of osteomalacia. A puzzling feature of all the above patients with bone disease and masked hyperparathyroidism is that published work consistently gives plasma-calcium levels in primary hyperparathyroidism with bone disease higher than concentrations found in those usually stone-forming patients without bone disease. Furthermore, the " with bone disease " patients have much higher ip.T.H. levels than the patients without bone disease. If P.T.H. increased vitamin-D requirements, as Woodhouse et al.13 suggested, the bonedisease patients should more often show masked
primary hyperparathyroidism,"
hypercalcaemia (i.e., normocalcxmia or only slightly raised plasma-calcium). The stone-forming normocalcaemic patients without bone disease also need further study along these lines. Perhaps from the practical diagnostic point of view we should strongly recommend that in all normocalcxmic patients in whom the other clinical evidence points to hyperparathyroidism with or without bone disease, the plasma-25-H.c.c. should be determined. We should for the time being assume that rachitic levels, say below 4 pg. per ml., invalidate the plasma-calcium determination which needs to be repeated after vitamin D has been given. We have in the past given rather empirically a dose of 2 mg. a day of ergocalciferol or cholecalciferol for 10 days to patients with ambiguous hypercalcaemia and have sometimes produced clear-cut hydrocortisone-resistant hypercalcaemia and confirmed later the presence of parathyroid adenoma. Such a test we now think has a logical basis and would be better monitored by plasma-25-H.c.c. as well as by plasma-calcium determinations. We thank the nurses, dietitians, and biochemists of the metabolic ward for their help in these investigations. The P.T.H. assays were done by Miss Susan Heels.
Requests
for
reprints should be addressed
to
C. E. D.
REFERENCES 1. McGeown, M. G., Morrison, E. Postgrad. med. J. 1959, 35, 330. 2. Vaishnava, H., Rizvi, S. N. A. Am. J. Med. 1969, 46, 640. 3. Wills, M. R., Pak, C. Y. C., Hammond, W. G., Bartler, F. C. ibid. 1969, 47, 384. 4. Keynes, W. M., Caird, F. I. Br. med. J. 1970, i, 208. 5. Dent, C. E. ibid. 1962, ii, 1419. 6. Berry, E. M., Gupta, M. M., Turner, S. J., Burns, R. R. ibid. 1973, iv, 640. 7. Berson, S. A., Yalow, R. S., Aurbach, S. U., Potts, J. T. Proc. natn. Acad. Sci. U.S.A. 1963, 49, 613. 8. Haddad, J. G., Chyu, K. J. J. clin. Endocr. Metab. 1971, 33, 992. 9. Dick, M. Gut, 1969, 10, 408. 10. Dent, C. E., Stamp, T. C. B. Q. Jl Med. 1971, 40, 303. 11. Lichtwitz, A., de Seze, S., Hioco, D., Bordier, P., Mazabrand, A. Presse méd. 1956, 64, 2031. 12. Wills, M. R. Lancet, 1971, i, 849. 13. Woodhouse, N. J. Y., Doyle, F. H., Joplin, G. F. ibid. 1971, ii, 283. 14. Davis, D. R., Dent, C. E., Watson, L. Br. med. J. 1968, iii, 395.
AUDITORY EVOKED RESPONSES IN MULTIPLE SCLEROSIS KATHLEEN ROBINSON
PETER RUDGE
Department of Clinical Neurophysiology and Medical Research Council Hearing and Balance Unit, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG The early components of the auditory evoked responses (waves I-V) have been studied in 30 patients with multiple sclerosis. There were abnormalities in 22 patients. All patients with an internuclear ophthalmoplegia and half those with no detectable brainstem abnormality had abnormal responses, although none was clinically deaf.
Summary
Introduction
diagnosis of multiple sclerosis is a clinical one depending on detection of multiple lesions within the THE
system white matter. A common neurological problem arises in patients presenting with a single lesion within the central nervous system—e.g., in the posterior column of the cord. In such cases detection of a second lesion would be of great diagnostic .value. Visual evoked responses (V.E.R.), recorded by averaging techniques through scalp electrodes, have proved useful in this respect,1 particularly since abnormalities of latency, but not of amplitude, persist after clinical recovery from retrobulbar neuritis, thus enabling the lesion to be detected long after the initial event. If similar increases in latency exist in other sensory pathways, additional diagnostic information might be obtained by studying these. In the auditory system 15 distinct components evoked by click stimuli can be recorded with scalp electrodes,and these have been classified into early (up to 8 msec.), middle (8-40 msec.), and late (50-250 msec.) latency groups.2 Of the early group the first component (i) arises from the eighth nerve and the next four components (ll-v) are thought to originate from brainstem These components, rather than those of nuclei 3 longer latency, were chosen for study since they are reliably recorded in healthy subjects and’ they are highly consistent from run to run.
central
nervous
Methods
Recording Two channels of the electroencephalogram (E.E.G.) were recorded from silver cup electrodes applied with collodion to the scalp at the vertex and to each mastoid. An earth electrode was similarly applied to the scalp at a position midway between the vertex and the inion. The electrodes were connected such that a positive-going potential at the vertex, relative to the mastoid, caused a downward deflection. The E.E.G. was amplified (Device’s physiological amplifiers type 3120) using a time constant of 0-2 sec. and high frequency cut off at 2-5 kHz. Clicks of 0-5 msec. duration were presented binaurally by a digital programmer (Digitimer Ltd, type 4030) through earphones to the subject, who was comfortably seated. Clicks of 957 dBC re 2 × 10-5 newtons per sq.m. sound pressure level (note-duration of click) were presented binaurally at a rate of 20 per sec. An averager (Biomac 1000, Data Laboratories Ltd), with a sweep duration of 40 msec., was triggered by the digital programmer to average the
1165 LATBNCY AND AMPLITUDE OF COMPONENTS
I, II, III, AND
V
(NORMAL
SUBJECTS)
an internuclear ophthalmoplegia and 1 had atypical ocular bobbing, indicating a definite brainstem lesion. Another 9 patients exhibited nystagmus, while the remainder had no evidence of a brainstem lesion. Apart from the first 4 patients, selected because they had a definite brainstem abnormality, the remainder were randomly chosen.
Results A typical record from a normal subject is shown in 1 A. The mean latencies and amplitudes, together with their standard deviations, for components I, n, ill,
fig. evoked responses. In all cases the result was the average of 512 responses. After the recording of an average response the store of the averager was punched onto paper tape, which was later read into a PDP 12 computer (Digital Equipment Corporation) and stored on magnetic tape for further analysis. Since the average evoked responses obtained from both pairs of electrodes in a subject were highly superimposable, measurements were taken for one pair
only. The average response, read from magnetic tape, was The smoothed by a three-point moving-average filter. latency was measured from the onset of the click to the downgoing (negative) peak of each of the first five components. The latency could be estimated to within 80 .sec. Amplitudes were measured from the preceding upgoing (positive) peak, for components II-V, and to the baseline, as estimated from the pre-stimulus signal level, for component I.
Subjects 19 hospital personnel of ages 20-56 years) acted as controls. There were
years (mean 32 11 males and 8
females. 30 patients,
aged 18-59 years (mean 35 years), comequal number of males and females, were studied. 3 of the patients had clinically probable, and the remainder clinically definite, multiple sclerosis 4 None
prising
was
an
deaf
on
clinical examination.
8 of the
patients had Fig. 2-Latency in
msec. (above) and amplitude in tiV (below) of component V from 30 patients with multiple sclerosis.
Values obtained from normal subjects indicated by broken lines (mean ±2 s.D.). Column A, subjects with a definite brainstem lesion; column B, subjects with nystagmus; and column C, parents with no brainstem abnormality detected clinically.
m sec.
Fig. I-Auditory evoked responses from normal subject (A) and patient with multiple sclerosis (B).
Components arrow.
i, n, III, and
v are
Horizontal axis, time in
indicated.
msec.
Click starts at Calibration 0 25 uV.
and v of normal controls are shown in the table. None of the values is more than 2 standard deviations (S.D.) from the mean. The largest of the five waves is component v. Since this also had the least relative variation of both amplitude and latency, it was selected to classify the records. Components n and iv were inconstant, iv often being absent. 22 of the 30 patients had significantly abnormal responses (>2 S.D.). Of these, 10 had an increase in latency of component v and 16 a decrease in amplitude of this component. 4 patients had both an increase in latency and a decrease in amplitude. An abnormal record is illustrated in fig. I B. Latency and amplitude data for all the patients are summarised in fig. 2. All the patients with internuclear ophthalmoplegia or ocular bobbing had abnormal responses (fig. 2 A). Five of these had increased latency. 7 of the 9 patients with nystagmus had abnormal responses, including 5 with increased latency and 4 with reduced amplitude (fig. 2 B). None of the patients without brainstem
1166
signs had an abnormal latency, although 6 of them (50%) had a significant decrease in amplitude (fig. 2 C). 5 of the 10 patients with delay of component v also had increased latency of component ill. 3 of these also had delays of wave n, but in 3 other patients this component (11) could not be identified. In no case was component I abnormal, and, in every case of abnormal latency of any component, wave v was also
delayed. Discussion
.
,
The auditory pathways from one cochlear end-organ involve the ipsilateral eighth nerve and cochlear nuclei. From these nuclei fibres pass to the olivary nuclei on both sides of the brainstem, then, via the lateral lemnisci, to, the inferior colliculi and the medial geniculate bodies. The first component of the auditory evoked response (A.E.R.) recorded by the scalp electrodes originates from activity of the eighth nerve. The later components (ll-v) arise in part from the sequential activity of the cochlear nuclei, olivary nuclei, inferior colliculi, and an area anterior to the colliculi.3 The potentials recorded are the sum of activity of many thousands of cells, and their form depends on the temporal pattern of activity of these cells. Demyelination of the tracts within the auditory pathways would be expected to delay the serial transmission of impulses to the various nuclear masses within these pathways and consequently alter the summation potentials recorded.5 The data presented here indicate that there are alterations in the form of the A.E.R. in a substantial proportion of patients with multiple sclerosis. In some cases there is considerable delay in the peak of wave v. This absolute increase in latency does not necessarily imply delays of this order in individual nerve-fibres. Clearly a lesion at a low level in such a serial system can alter all subsequent components. Thus all the patients with abnormal components n In this situation or ill had alteration of later waves. the term component v is no longer strictly correct since additional small waves (
diagnosis with primary hyperparathyroidism occurring by chance in a woman with anticonvulsant osteomalacia, but some may agree with us that this tertiary, with the adenoma the consequence of the anticonvulsant therapy. We have reported two other patients with both epilepsy and case
also
was
but did not then anticonvulsant that the consider therapy might be the cause. A new finding has come from the assays not available to earlier workers; plasma 25-H.C.C. levels were low in both our patients, thus independently confirming the presence of osteomalacia. A puzzling feature of all the above patients with bone disease and masked hyperparathyroidism is that published work consistently gives plasma-calcium levels in primary hyperparathyroidism with bone disease higher than concentrations found in those usually stone-forming patients without bone disease. Furthermore, the " with bone disease " patients have much higher ip.T.H. levels than the patients without bone disease. If P.T.H. increased vitamin-D requirements, as Woodhouse et al.13 suggested, the bonedisease patients should more often show masked
primary hyperparathyroidism,"
hypercalcaemia (i.e., normocalcxmia or only slightly raised plasma-calcium). The stone-forming normocalcaemic patients without bone disease also need further study along these lines. Perhaps from the practical diagnostic point of view we should strongly recommend that in all normocalcxmic patients in whom the other clinical evidence points to hyperparathyroidism with or without bone disease, the plasma-25-H.c.c. should be determined. We should for the time being assume that rachitic levels, say below 4 pg. per ml., invalidate the plasma-calcium determination which needs to be repeated after vitamin D has been given. We have in the past given rather empirically a dose of 2 mg. a day of ergocalciferol or cholecalciferol for 10 days to patients with ambiguous hypercalcaemia and have sometimes produced clear-cut hydrocortisone-resistant hypercalcaemia and confirmed later the presence of parathyroid adenoma. Such a test we now think has a logical basis and would be better monitored by plasma-25-H.c.c. as well as by plasma-calcium determinations. We thank the nurses, dietitians, and biochemists of the metabolic ward for their help in these investigations. The P.T.H. assays were done by Miss Susan Heels.
Requests
for
reprints should be addressed
to
C. E. D.
REFERENCES 1. McGeown, M. G., Morrison, E. Postgrad. med. J. 1959, 35, 330. 2. Vaishnava, H., Rizvi, S. N. A. Am. J. Med. 1969, 46, 640. 3. Wills, M. R., Pak, C. Y. C., Hammond, W. G., Bartler, F. C. ibid. 1969, 47, 384. 4. Keynes, W. M., Caird, F. I. Br. med. J. 1970, i, 208. 5. Dent, C. E. ibid. 1962, ii, 1419. 6. Berry, E. M., Gupta, M. M., Turner, S. J., Burns, R. R. ibid. 1973, iv, 640. 7. Berson, S. A., Yalow, R. S., Aurbach, S. U., Potts, J. T. Proc. natn. Acad. Sci. U.S.A. 1963, 49, 613. 8. Haddad, J. G., Chyu, K. J. J. clin. Endocr. Metab. 1971, 33, 992. 9. Dick, M. Gut, 1969, 10, 408. 10. Dent, C. E., Stamp, T. C. B. Q. Jl Med. 1971, 40, 303. 11. Lichtwitz, A., de Seze, S., Hioco, D., Bordier, P., Mazabrand, A. Presse méd. 1956, 64, 2031. 12. Wills, M. R. Lancet, 1971, i, 849. 13. Woodhouse, N. J. Y., Doyle, F. H., Joplin, G. F. ibid. 1971, ii, 283. 14. Davis, D. R., Dent, C. E., Watson, L. Br. med. J. 1968, iii, 395.
AUDITORY EVOKED RESPONSES IN MULTIPLE SCLEROSIS KATHLEEN ROBINSON
PETER RUDGE
Department of Clinical Neurophysiology and Medical Research Council Hearing and Balance Unit, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG The early components of the auditory evoked responses (waves I-V) have been studied in 30 patients with multiple sclerosis. There were abnormalities in 22 patients. All patients with an internuclear ophthalmoplegia and half those with no detectable brainstem abnormality had abnormal responses, although none was clinically deaf.
Summary
Introduction
diagnosis of multiple sclerosis is a clinical one depending on detection of multiple lesions within the THE
system white matter. A common neurological problem arises in patients presenting with a single lesion within the central nervous system—e.g., in the posterior column of the cord. In such cases detection of a second lesion would be of great diagnostic .value. Visual evoked responses (V.E.R.), recorded by averaging techniques through scalp electrodes, have proved useful in this respect,1 particularly since abnormalities of latency, but not of amplitude, persist after clinical recovery from retrobulbar neuritis, thus enabling the lesion to be detected long after the initial event. If similar increases in latency exist in other sensory pathways, additional diagnostic information might be obtained by studying these. In the auditory system 15 distinct components evoked by click stimuli can be recorded with scalp electrodes,and these have been classified into early (up to 8 msec.), middle (8-40 msec.), and late (50-250 msec.) latency groups.2 Of the early group the first component (i) arises from the eighth nerve and the next four components (ll-v) are thought to originate from brainstem These components, rather than those of nuclei 3 longer latency, were chosen for study since they are reliably recorded in healthy subjects and’ they are highly consistent from run to run.
central
nervous
Methods
Recording Two channels of the electroencephalogram (E.E.G.) were recorded from silver cup electrodes applied with collodion to the scalp at the vertex and to each mastoid. An earth electrode was similarly applied to the scalp at a position midway between the vertex and the inion. The electrodes were connected such that a positive-going potential at the vertex, relative to the mastoid, caused a downward deflection. The E.E.G. was amplified (Device’s physiological amplifiers type 3120) using a time constant of 0-2 sec. and high frequency cut off at 2-5 kHz. Clicks of 0-5 msec. duration were presented binaurally by a digital programmer (Digitimer Ltd, type 4030) through earphones to the subject, who was comfortably seated. Clicks of 957 dBC re 2 × 10-5 newtons per sq.m. sound pressure level (note-duration of click) were presented binaurally at a rate of 20 per sec. An averager (Biomac 1000, Data Laboratories Ltd), with a sweep duration of 40 msec., was triggered by the digital programmer to average the
1165 LATBNCY AND AMPLITUDE OF COMPONENTS
I, II, III, AND
V
(NORMAL
SUBJECTS)
an internuclear ophthalmoplegia and 1 had atypical ocular bobbing, indicating a definite brainstem lesion. Another 9 patients exhibited nystagmus, while the remainder had no evidence of a brainstem lesion. Apart from the first 4 patients, selected because they had a definite brainstem abnormality, the remainder were randomly chosen.
Results A typical record from a normal subject is shown in 1 A. The mean latencies and amplitudes, together with their standard deviations, for components I, n, ill,
fig. evoked responses. In all cases the result was the average of 512 responses. After the recording of an average response the store of the averager was punched onto paper tape, which was later read into a PDP 12 computer (Digital Equipment Corporation) and stored on magnetic tape for further analysis. Since the average evoked responses obtained from both pairs of electrodes in a subject were highly superimposable, measurements were taken for one pair
only. The average response, read from magnetic tape, was The smoothed by a three-point moving-average filter. latency was measured from the onset of the click to the downgoing (negative) peak of each of the first five components. The latency could be estimated to within 80 .sec. Amplitudes were measured from the preceding upgoing (positive) peak, for components II-V, and to the baseline, as estimated from the pre-stimulus signal level, for component I.
Subjects 19 hospital personnel of ages 20-56 years) acted as controls. There were
years (mean 32 11 males and 8
females. 30 patients,
aged 18-59 years (mean 35 years), comequal number of males and females, were studied. 3 of the patients had clinically probable, and the remainder clinically definite, multiple sclerosis 4 None
prising
was
an
deaf
on
clinical examination.
8 of the
patients had Fig. 2-Latency in
msec. (above) and amplitude in tiV (below) of component V from 30 patients with multiple sclerosis.
Values obtained from normal subjects indicated by broken lines (mean ±2 s.D.). Column A, subjects with a definite brainstem lesion; column B, subjects with nystagmus; and column C, parents with no brainstem abnormality detected clinically.
m sec.
Fig. I-Auditory evoked responses from normal subject (A) and patient with multiple sclerosis (B).
Components arrow.
i, n, III, and
v are
Horizontal axis, time in
indicated.
msec.
Click starts at Calibration 0 25 uV.
and v of normal controls are shown in the table. None of the values is more than 2 standard deviations (S.D.) from the mean. The largest of the five waves is component v. Since this also had the least relative variation of both amplitude and latency, it was selected to classify the records. Components n and iv were inconstant, iv often being absent. 22 of the 30 patients had significantly abnormal responses (>2 S.D.). Of these, 10 had an increase in latency of component v and 16 a decrease in amplitude of this component. 4 patients had both an increase in latency and a decrease in amplitude. An abnormal record is illustrated in fig. I B. Latency and amplitude data for all the patients are summarised in fig. 2. All the patients with internuclear ophthalmoplegia or ocular bobbing had abnormal responses (fig. 2 A). Five of these had increased latency. 7 of the 9 patients with nystagmus had abnormal responses, including 5 with increased latency and 4 with reduced amplitude (fig. 2 B). None of the patients without brainstem
1166
signs had an abnormal latency, although 6 of them (50%) had a significant decrease in amplitude (fig. 2 C). 5 of the 10 patients with delay of component v also had increased latency of component ill. 3 of these also had delays of wave n, but in 3 other patients this component (11) could not be identified. In no case was component I abnormal, and, in every case of abnormal latency of any component, wave v was also
delayed. Discussion
.
,
The auditory pathways from one cochlear end-organ involve the ipsilateral eighth nerve and cochlear nuclei. From these nuclei fibres pass to the olivary nuclei on both sides of the brainstem, then, via the lateral lemnisci, to, the inferior colliculi and the medial geniculate bodies. The first component of the auditory evoked response (A.E.R.) recorded by the scalp electrodes originates from activity of the eighth nerve. The later components (ll-v) arise in part from the sequential activity of the cochlear nuclei, olivary nuclei, inferior colliculi, and an area anterior to the colliculi.3 The potentials recorded are the sum of activity of many thousands of cells, and their form depends on the temporal pattern of activity of these cells. Demyelination of the tracts within the auditory pathways would be expected to delay the serial transmission of impulses to the various nuclear masses within these pathways and consequently alter the summation potentials recorded.5 The data presented here indicate that there are alterations in the form of the A.E.R. in a substantial proportion of patients with multiple sclerosis. In some cases there is considerable delay in the peak of wave v. This absolute increase in latency does not necessarily imply delays of this order in individual nerve-fibres. Clearly a lesion at a low level in such a serial system can alter all subsequent components. Thus all the patients with abnormal components n In this situation or ill had alteration of later waves. the term component v is no longer strictly correct since additional small waves (
