Animal Model of Acoustic Neuroma Jonathan Chinn, MD, Josef Miller, PhD As part of an effort to develop a longterm animal model simulating the effects of acoustic neuromas, a series of shortterm electrophysiological experiments were performed in the cat. The eighth nerve, as it exits the internal auditory meatus, was exposed and a silicone balloon catheter secured over the nerve. Pure tones and clicks were introduced ipsilaterally and primary evoked potentials were recorded from the contralateral auditory cortex. Alterations in the evoked potentials were examined as the balloons were inflated and deflated.
its early recognition by Sandifort in 1777, acoustic neuromas have drawn the interest of many in¬
Since
vestigators.1-2 Diagnosis, particularly
in the last few years, has achieved a considerable degree of sophistication. Contrast cysternography, polytomog¬
raphy, perilymph protein analysis, and modern audiometry have allowed
the detection and identification of these tumors at earlier, surgically less formidable stages of development.2 Parallel surgical advances have con¬ siderably improved the 80% operative mortality that followed Charles Bal¬ ance's pioneering effort in 1894.1·2 Despite the advances in diagnosis and treatment there is still much to
Accepted for publication Sept 20, 1974. From the University of Washington School of
Medicine and the US Public Health Service, Seattle (Dr. Chinn), and the departments of otolaryngology, physiology, and biophysics, the University of Washington, Seattle (Dr. Miller). Reprint requests to the Department of Otolaryngology, University of Washington School of Medicine, Seattle, WA 98195 (Dr. Miller).
Several reproducible phenomena were (1) contact between the silicone balloons and eighth nerves resulted in substantial reductions in the evoked potential; (2) there was a further reduction recorded:
in the evoked potential with inflation of the indwelling balloons; and (3) there was a prolongation of the latency period between auditory stimulation and the onset of the evoked potential with balloon inflation. All of these phenomena were reversed when either the contact was broken or balloons deflated.
be learned of the basic pathophysiol¬ ogy of these lesions. Although there is a considerable fund of information on the effects of compression on periph¬ eral nerves'"7 the effects of mass le¬ sions on the eighth nerve have not been studied experimentally. This report is the result of an at¬ tempt to develop an animal model for the study of the short-term effects of simulated mass lesions of the eighth nerve on auditory system function. METHODS
Subjects Healthy adult cats from 2 to 4 kg were used in this study. Otoscopie examination was performed in all animals in order to screen for pathologic conditions that might interfere with the study. Of the 25 cats studied, data reported in this report are based on observations on the last 20 in which the procedures used were constant.
Surgical
Procedure
Initial anesthesia was achieved using 35 mg/kg of pentobarbital sodium (Nembutal) administered intraperitoneally. Sup-
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
plemental Pentobarbital, given intrave¬ nously, was used to abolish the pain
response. After anesthetization the ani¬ mals were shaven and an intravenous cath¬ eter inserted. Tracheostomy was per¬ formed using a small "Y" connector as tracheostomy tube. The tracheostomy was generally left open to room air. In some studies, carried over several hours, supple¬ mental oxygen and occasionally assisted respirations were used to maintain a more physiological preparation. The cats were then placed on a warming pad, a rectal thermoprobe inserted, and body tempera¬ ture maintained at approximately 37 C. A small animal head holder was em¬ ployed to stabilize the cats' heads. The skull over the occipital lobe on one side was exposed and then opened with a dental drill and rongeurs. With the dura intact the occipital lobe could be readily displaced anteriorly to expose the bony tentorium overlying the cat cerebellum. The cerebel¬ lum was exposed by drilling and rongeuring away the covering tentorium and open¬ ing the dura. With this exposure the posterior face of the temporal bone was identified and cerebellum adjacent to it re¬ moved by suction. In the depths of this surgical defect the eighth nerve could be seen coursing between the internal audi¬ tory meatus and brain stem. With the eighth nerve thus exposed, balloon cathe¬ ters could then be secured in place. The balloons were fashioned from .005inch thick silicone (Silastic) sheeting tied and epoxied to 1-mm diameter blunt nee¬ dles. Their deflated diameter was 2 to 3 mm and their inflated diameter 5 to 7 mm. Physiological saline was used to inflate the balloons. These balloons were placed visu¬ ally over exposed eighth nerves and se¬ cured in place by cementing them to the skull. In experiments designed specifically to investigate the role of contact between the balloon and the nerve in evoked poten-
tial alteration, small pieces of silicone sheeting were placed very gently directly on exposed eighth nerves. Preparation for recording evoked poten¬ tials was made by exposing the contralat¬ eral auditory cortex. A .02-inch diameter platinum electrode was then positioned vi¬ sually to contact sites in auditory area AI.
Reduction in Evoked Potential* Due to Contact Evoked Potential Evoked Potential Without Eighth With Eighth Cat Nerve Manipulation Nerve Manipulation % Reduction 425 280 34 105
Electrophysiological Preparation The evoked potential was recorded monopolarly with an indifferent electrode attached to the skin edge at the site of in¬ cision. The electrode was then connected to a high-impedance probe (Grass model No. HIP511A) and through a preamplifier (Grass model No. P511) to an oscilloscope (Tektronix type 565). In each experiment 50µ calibration pulses and 500 cycles per second timing signals were recorded. Audi¬ tory stimuli were delivered via a closed
168
97 60 143
43 15
159
96
40
After 10 min stabilization Cotton moistened with saline on eighth nerve Silicone sheet on
113
13 15
Balloon on eighth nerve Silicone sheet + balloon
150
17 40
Silicone sheet
138
45
Silicone sheet + balloon
87 74
13 38
eighth 101 133
on
11
106 250
100 120
duration at 3 v, were used to generate clicks at a rate of 1/sec. In a few experi¬ ments pure-tone stimuli of 100 msec dura¬ tion and 5 msec risefall time were used.
43
325
200
38 a 29% SD ± 14%
nerve
Silicone sheet
on
nerve
Silicone sheet + balloon on
19
on
nerve
eighth
eighth 68
nerve _
on
12 13
nerve
eighth
eighth
system by
a high-performance speaker (PDL-600) and secured by suture to the cartilaginous external auditory canal. Square wave voltage charges of .2 msec
Comment
eighth
nerve
Evoked potentials recorded in microvolts.
Experimental Procedure The site of maximum auditory evoked potential was determined for each animal. For uniformity and consistency this site was used in reporting all data. Further, since marked alterations in the evoked po¬ tential occurred with even minor changes in electrode position, once placed, the elec¬ trode was not moved until the experiment
completed. Recordings of the evoked potential were then made before eighth nerve exposure, after eighth nerve exposure, after the bal¬ loon or silicone sheeting placement, and was
with inflation and deflation of the balloons. When feasible, the effects of repeated in¬ flations and deflations were recorded. Recordings were made routinely immedi¬ ately on eighth nerve manipulation, and at one, two, three, and five minutes. There¬ after, recordings were made until the evoked potential had stabilized. Some ad¬ justment in the amount of inflation was made at times since it became apparent rapidly that when the evoked potential was completely abolished by inflation perma¬ nent damage would ensue without any re¬ covery in evoked potential within the pe¬ riod of observation. The preparations remained physiologically stable for six to ten hours. In some experiments high (4,000 or 6,000 cps), middle (1,000 cps), and low (500 cps) frequency tones were used in addition to
and with placement Fig 1.—Evoked potential alterations due to balloon "contact") click stimuli. In all (ie, other aspects the proce¬ and evoked potential alterations with bal¬ inflation and deflation. Comparison of latencydure was the same. loon inflation and deflation.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
Recording
and Data
Oscilloscope displays
35-mm film and
Analysis
were
recorded
on
reader. Latency was measured from stimulus arti¬ fact to the initial onset of the evoked po¬ tential using the 500 cps timing signal as
analyzed on a film
and deflation. The inverse function of la¬
superimposed over amplitude graphs to illustrate their parallel behavior. tency
was
RESULTS General Observations The most common site from which maximum primary evoked potential was recorded was posteroinferior auditory cortex AI near the tip of the posterior ectosylvian sulcus. The other site yielding a maximal record¬ ing was anterosuperior AI. The base line values for the evoked potential ranged from 50µ to 500µ among the different animals. For any given ani¬ mal and recording site, however, the range of evoked potential was stable. The recorded evoked potentials were consistently of a biphasic positivenegative wave form. The latency be¬ tween auditory stimulation and onset of evoked potential ranged from 6 to a
10
sistently and reproducibly by the
in¬ flation of the balloon catheters. The drop in amplitude was greater than that observed to be due to contact. Figures 1 to 3 illustrate this finding. In Fig 1, the initial inflation did not cause a drop in the evoked potential, in fact there was actually a slight in¬ crease. However, with further in¬ crease in the amount of inflation there was an immediate and marked
reduction in the evoked potential. This indicates that there is probably some minimal inflation necessary to elicit this reduction in evoked po¬ tential. A small additional inflation did not alter the evoked potential greatly. With deflation of the balloon there was an increase in the evoked potential almost to preinflation levels. Figures 2 and 3 are similar to Fig 1 in that there was a reduction in
msec.
Contact Phenomena
With contact between the balloons and the eighth nerves there was a substantial reduction in evoked po¬ tential. This "contact" phenomena was examined in eight animals with special efforts made to minimize any pressure effects that might be attend¬ ant with balloon placement. The re¬ sults are tabulated in the Table and an example graphically shown in Fig 1. The average reduction in the evoked potential due to eighth nerve manipulation (ie, placement of sili¬ cone sheeting, balloon contact, or both) was 29% with a SD of 14%. As shown in Fig 1, the effect was imme¬ diate and dramatic. From the Table it is seen that this reduction was not strictly due to pressure, since very gentle placement of pieces of silicone sheeting alone resulted in a substan¬ tial reduction of the evoked poten¬ tial (eg, 40%, 40%, and 38%). Further, since silicone is relatively inert and saline-moistened cotton alone in con¬ tact with eighth nerves resulted in evoked potential reduction, the phe¬ nomena is probably independent of the balloon material.
Fig 2.—More profound
Fig 3.—Complete
reduction in evoked
loss of evoked
potential
with second inflation of balloon.
potential with balloon inflation.
Amplitude Alterations The amplitude of the evoked poten¬ tial was found to be reduced con-
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
evoked
potential with
inflation and potential with deflation. Additionally the phenom¬ ena as a function of time and eighth nerve manipulation is noted. The eighth nerve apparently became more susceptible to inflation; for as shown in Fig 2, a second inflation with the same volume as the first inflation re¬ sulted in a more profound reduction in evoked potential. Figures 2 and 3 also show that when inflation was great enough to abolish the evoked potential the return on deflation was slowed or there was no return at all. In many instances the amount of in¬ flation required to achieve a revers¬ ible reduction in evoked potential was limited. Beyond this point small addi¬ tional inflation completely and per¬ manently abolished the evoked poten¬ tial. Figure 4 illustrates a preparation where the balloon failed to maintain volume. After inflation there was a slow spontaneous deflation and a par¬ some
return in evoked
allel return in the evoked potential. However, with each inflation there was once again a substantial reduc¬ tion in the evoked potential.
In Fig 2 to 4 pure tones as well as clicks were used as auditory stimuli. No consistent differences in the evoked responses were noted between clicks and pure tones.
Fig 4.—Balloon
Latency
Alterations
With inflation the latency between auditory stimulation and onset of evoked potential was prolonged. The changes were not dramatic but con¬ sistent. In Fig 1 and 4 the reciprocal of the latency (in milliseconds) is plotted over amplitude alterations. It is apparent that prolongation of la¬ tency paralleled evoked potential re¬
duction. Further, with deflation and return of the evoked potential the la¬ tency returned toward normal. Two other observations were made. (1) The prolongation in latency did not occur with balloon contact. (2) It was not possible to show the latency change to be a continuous function of balloon inflation, rather latency changed in a stepwise fashion. There was either a moderate, but definite increase in the latency or total block¬ ade of neural transmission and there¬ fore no recordable latency alteration. COMMENT The finding of two foci of high-am¬ plitude evoked potential in auditory cortex AI is in agreement with the observations of other investigators." The base line values recorded for both latency and amplitude of evoked po¬ tential are also in agreement with the findings of other investigators."1" The figure given for the average re-
that failed to maintain Inflation
(see text).
duction in evoked potential due to "contact" and its standard deviation must be qualified since it is only accu¬ rate where their values were greater than zero. In some instances, no mat¬ ter how gentle, balloon placement abolished the evoked potential. If these instances are considered the average reduction and standard de¬ viation would of course be greater. Two observations suggest the distinctiveness of the "contact" phenom¬ ena from loss due to balloon inflation. (1) Even the most careful placement of silicone sheeting resulted in sub¬ stantial evoked potential reductions. (2) With "contact" there was no alter¬ ation in latency as seen with balloon inflation. This suggests that the evoked potential reduction due to con¬ tact is distinct from that due to bal¬ loon inflation since the latter is coupled to latency alterations and the former is not. In the Table it is seen that balloon placement over previously placed sili¬ cone sheeting results in an additional reduction in evoked potential of ap¬ proximately 5%. This additional re¬ duction is probably due to the pres¬ sure of the nerve attendant with balloon placement. "Contact" reduc¬ tion is negated by the interposed sili¬ cone sheeting. The magnitude of this additional evoked potential reduction is small in comparison to that ob¬ served with contact and with balloon inflation and, therefore, is not a ma¬ jor factor in evoked-potential altera¬ tions. The alterations in evoked potential observed in this study can be com¬ pared with observations from periph¬ eral nerve studies on the effect of compression on nerve function. In the early 1940s Weiss and Davis' studied the effects of compression on isolated rat sciatic nerves. They found that compression resulted in a rapid and progressive fall in action potential and that the effect was reversible on release of compression. Although the present study deals with a special sensory
nerve vs a
motor
nerve
(sci¬
is some evidence that motor and sensory nerves are differ¬ entially sensitive to compression,4 the basic effect on nerve conduction is the
atic) and there
same.
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Two other observations are perti¬ (1) There may be heightened nerve excitability as the initial re¬ sponse to nerve manipulation and to ischemia."; Perhaps the increase in evoked potential following balloon in¬ flation seen in Fig 1 to 3 can be ex¬ plained by such heightened nerve ex¬ citability. (2) Damaged nerve fibers are more susceptible to ischemia.11 Certainly, no matter how carefully performed there must be some ele¬ ment of eighth nerve injury in the preparation of these animals. In addi¬ tion, there is probably local ischemia associated with balloon inflation and, therefore, a more profound reduction in evoked potential would be expected with each subsequent balloon infla¬ tion. That this is the case is illus¬ trated by Fig 2 and 3. In Fig 2 the second inflation results in a greater reduction in evoked potential as well as a delayed (for 500 and 4,000 cps) and reduced return on deflation. In Fig 3 the amount of return with de¬ flation is reduced and there is a delay in return of the evoked potential to clicks. An additional observation made in this study relative to amplitude alter¬ ations was that in several prepara¬ tions even the most minor eighth nerve manipulation resulted in com¬ plete loss of the evoked potential. Al¬ though more often than not there was no return in evoked potential with nent.
deflation, this short-term study was limited by the six to ten hours the preparation remained physiological. Return of function after compression
injury to
nerves
may
require days
mals could then give the final behav¬ ioral correlates to these simulated
eighth
nerve
tumors.
or
weeks3 and would be missed in these short-term experiments. This increase in latency recorded in this study may be related to the dif¬ ferential effect that compression has on nerve fibers of differing size.1' Con¬ duction of the fastest impulses are in¬ terrupted before complete blockade.11 This would result in an apparent re¬ duced conduction velocity and prolon¬ gation in latency. Since a similar mechanism is probably the explana¬ tion for the amplitude alterations seen, the two functions would be ex¬ pected to parallel one another. That this is the case is shown in Fig 1 and 4 with amplitude plotted over the recip¬ rocal of latency. This is a preliminary study and much more is to be learned of the ba¬ sic pathophysiology of eighth nerve lesions using this animal model and its extension the long-term prepara¬ tion. The question of the contribution of vascular occlusion to auditory sys¬ tem function alteration could be ap¬ proached with perfusion studies in conjunction with electrophysiological studies in these preparations. Fur¬ ther, histopathological examination would be necessary to evaluate any ischemie alterations of inner ear even
anatomy. Auditory conditioned ani¬
"
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This study was supported by training grant No. 5T01 NS 05553, from the National Institute of Neurological Diseases and Stroke, the Na¬ tional Institutes of Health, and by grant No. NS08181 from the National Institutes of Health.
References 1. Pool JL, Pava AA: Acoustic Nerve Tumors: and Treatment. Springfield, Ill, Charles C Thomas Publishers, 1970. 2. Cushing H: Tumors of the Nervus Acusticus. Philadelphia, WB Saunders Co, 1971. 3. Gelfan S, Tarlov IM: Physiology of spinal cord, nerve root and peripheral nerve compression. Am J Physiol 184-85:217-229, 1956. 4. Sunderland S: Nerves and Nerve Injuries: Part II. Degeneration Regeneration; A Classification of Nerve Injury. Baltimore, Williams & Wilkins Co, 1968. 5. Weiss P, Davis H: Pressure block in nerves provided with arterial sleeves. J Neurophysiol 6:269-286, 1943. 6. Porter EL, Wharton PS: Irritability of mammalian nerve following ischemia. J Neurophysiol 12:109-116, 1949. 7. Denny-Brown D, Brenner C: Paralysis of nerve induced by direct pressure and by tourniquet. Arch Neurol Psychiatry 51:1-26, 1944. 8. Miller J, Ryan A: Effects of medial geniculate lesions on click-evoked potentials in the cat. Exp Neurol 39:103-111, 1973. 9. Hawkins JE Jr: Cortical responses to click stimulation. Am J Physiol 133:321-322, 1941. 10. Ades HW: Central auditory mechanisms, in Field J (ed): Neurophysiology. Washington, DC, American Physiological Society, 1959, vol 1, chapt 24. 11. Denny-Brown D, Brenner C: Lesions in peripheral nerve resulting from compression by spring clip. Arch Neurol Psychiatry 52:1-19, 1944.
Early Diagnosis
its early recognition by Sandifort in 1777, acoustic neuromas have drawn the interest of many in¬
Since
vestigators.1-2 Diagnosis, particularly
in the last few years, has achieved a considerable degree of sophistication. Contrast cysternography, polytomog¬
raphy, perilymph protein analysis, and modern audiometry have allowed
the detection and identification of these tumors at earlier, surgically less formidable stages of development.2 Parallel surgical advances have con¬ siderably improved the 80% operative mortality that followed Charles Bal¬ ance's pioneering effort in 1894.1·2 Despite the advances in diagnosis and treatment there is still much to
Accepted for publication Sept 20, 1974. From the University of Washington School of
Medicine and the US Public Health Service, Seattle (Dr. Chinn), and the departments of otolaryngology, physiology, and biophysics, the University of Washington, Seattle (Dr. Miller). Reprint requests to the Department of Otolaryngology, University of Washington School of Medicine, Seattle, WA 98195 (Dr. Miller).
Several reproducible phenomena were (1) contact between the silicone balloons and eighth nerves resulted in substantial reductions in the evoked potential; (2) there was a further reduction recorded:
in the evoked potential with inflation of the indwelling balloons; and (3) there was a prolongation of the latency period between auditory stimulation and the onset of the evoked potential with balloon inflation. All of these phenomena were reversed when either the contact was broken or balloons deflated.
be learned of the basic pathophysiol¬ ogy of these lesions. Although there is a considerable fund of information on the effects of compression on periph¬ eral nerves'"7 the effects of mass le¬ sions on the eighth nerve have not been studied experimentally. This report is the result of an at¬ tempt to develop an animal model for the study of the short-term effects of simulated mass lesions of the eighth nerve on auditory system function. METHODS
Subjects Healthy adult cats from 2 to 4 kg were used in this study. Otoscopie examination was performed in all animals in order to screen for pathologic conditions that might interfere with the study. Of the 25 cats studied, data reported in this report are based on observations on the last 20 in which the procedures used were constant.
Surgical
Procedure
Initial anesthesia was achieved using 35 mg/kg of pentobarbital sodium (Nembutal) administered intraperitoneally. Sup-
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
plemental Pentobarbital, given intrave¬ nously, was used to abolish the pain
response. After anesthetization the ani¬ mals were shaven and an intravenous cath¬ eter inserted. Tracheostomy was per¬ formed using a small "Y" connector as tracheostomy tube. The tracheostomy was generally left open to room air. In some studies, carried over several hours, supple¬ mental oxygen and occasionally assisted respirations were used to maintain a more physiological preparation. The cats were then placed on a warming pad, a rectal thermoprobe inserted, and body tempera¬ ture maintained at approximately 37 C. A small animal head holder was em¬ ployed to stabilize the cats' heads. The skull over the occipital lobe on one side was exposed and then opened with a dental drill and rongeurs. With the dura intact the occipital lobe could be readily displaced anteriorly to expose the bony tentorium overlying the cat cerebellum. The cerebel¬ lum was exposed by drilling and rongeuring away the covering tentorium and open¬ ing the dura. With this exposure the posterior face of the temporal bone was identified and cerebellum adjacent to it re¬ moved by suction. In the depths of this surgical defect the eighth nerve could be seen coursing between the internal audi¬ tory meatus and brain stem. With the eighth nerve thus exposed, balloon cathe¬ ters could then be secured in place. The balloons were fashioned from .005inch thick silicone (Silastic) sheeting tied and epoxied to 1-mm diameter blunt nee¬ dles. Their deflated diameter was 2 to 3 mm and their inflated diameter 5 to 7 mm. Physiological saline was used to inflate the balloons. These balloons were placed visu¬ ally over exposed eighth nerves and se¬ cured in place by cementing them to the skull. In experiments designed specifically to investigate the role of contact between the balloon and the nerve in evoked poten-
tial alteration, small pieces of silicone sheeting were placed very gently directly on exposed eighth nerves. Preparation for recording evoked poten¬ tials was made by exposing the contralat¬ eral auditory cortex. A .02-inch diameter platinum electrode was then positioned vi¬ sually to contact sites in auditory area AI.
Reduction in Evoked Potential* Due to Contact Evoked Potential Evoked Potential Without Eighth With Eighth Cat Nerve Manipulation Nerve Manipulation % Reduction 425 280 34 105
Electrophysiological Preparation The evoked potential was recorded monopolarly with an indifferent electrode attached to the skin edge at the site of in¬ cision. The electrode was then connected to a high-impedance probe (Grass model No. HIP511A) and through a preamplifier (Grass model No. P511) to an oscilloscope (Tektronix type 565). In each experiment 50µ calibration pulses and 500 cycles per second timing signals were recorded. Audi¬ tory stimuli were delivered via a closed
168
97 60 143
43 15
159
96
40
After 10 min stabilization Cotton moistened with saline on eighth nerve Silicone sheet on
113
13 15
Balloon on eighth nerve Silicone sheet + balloon
150
17 40
Silicone sheet
138
45
Silicone sheet + balloon
87 74
13 38
eighth 101 133
on
11
106 250
100 120
duration at 3 v, were used to generate clicks at a rate of 1/sec. In a few experi¬ ments pure-tone stimuli of 100 msec dura¬ tion and 5 msec risefall time were used.
43
325
200
38 a 29% SD ± 14%
nerve
Silicone sheet
on
nerve
Silicone sheet + balloon on
19
on
nerve
eighth
eighth 68
nerve _
on
12 13
nerve
eighth
eighth
system by
a high-performance speaker (PDL-600) and secured by suture to the cartilaginous external auditory canal. Square wave voltage charges of .2 msec
Comment
eighth
nerve
Evoked potentials recorded in microvolts.
Experimental Procedure The site of maximum auditory evoked potential was determined for each animal. For uniformity and consistency this site was used in reporting all data. Further, since marked alterations in the evoked po¬ tential occurred with even minor changes in electrode position, once placed, the elec¬ trode was not moved until the experiment
completed. Recordings of the evoked potential were then made before eighth nerve exposure, after eighth nerve exposure, after the bal¬ loon or silicone sheeting placement, and was
with inflation and deflation of the balloons. When feasible, the effects of repeated in¬ flations and deflations were recorded. Recordings were made routinely immedi¬ ately on eighth nerve manipulation, and at one, two, three, and five minutes. There¬ after, recordings were made until the evoked potential had stabilized. Some ad¬ justment in the amount of inflation was made at times since it became apparent rapidly that when the evoked potential was completely abolished by inflation perma¬ nent damage would ensue without any re¬ covery in evoked potential within the pe¬ riod of observation. The preparations remained physiologically stable for six to ten hours. In some experiments high (4,000 or 6,000 cps), middle (1,000 cps), and low (500 cps) frequency tones were used in addition to
and with placement Fig 1.—Evoked potential alterations due to balloon "contact") click stimuli. In all (ie, other aspects the proce¬ and evoked potential alterations with bal¬ inflation and deflation. Comparison of latencydure was the same. loon inflation and deflation.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
Recording
and Data
Oscilloscope displays
35-mm film and
Analysis
were
recorded
on
reader. Latency was measured from stimulus arti¬ fact to the initial onset of the evoked po¬ tential using the 500 cps timing signal as
analyzed on a film
and deflation. The inverse function of la¬
superimposed over amplitude graphs to illustrate their parallel behavior. tency
was
RESULTS General Observations The most common site from which maximum primary evoked potential was recorded was posteroinferior auditory cortex AI near the tip of the posterior ectosylvian sulcus. The other site yielding a maximal record¬ ing was anterosuperior AI. The base line values for the evoked potential ranged from 50µ to 500µ among the different animals. For any given ani¬ mal and recording site, however, the range of evoked potential was stable. The recorded evoked potentials were consistently of a biphasic positivenegative wave form. The latency be¬ tween auditory stimulation and onset of evoked potential ranged from 6 to a
10
sistently and reproducibly by the
in¬ flation of the balloon catheters. The drop in amplitude was greater than that observed to be due to contact. Figures 1 to 3 illustrate this finding. In Fig 1, the initial inflation did not cause a drop in the evoked potential, in fact there was actually a slight in¬ crease. However, with further in¬ crease in the amount of inflation there was an immediate and marked
reduction in the evoked potential. This indicates that there is probably some minimal inflation necessary to elicit this reduction in evoked po¬ tential. A small additional inflation did not alter the evoked potential greatly. With deflation of the balloon there was an increase in the evoked potential almost to preinflation levels. Figures 2 and 3 are similar to Fig 1 in that there was a reduction in
msec.
Contact Phenomena
With contact between the balloons and the eighth nerves there was a substantial reduction in evoked po¬ tential. This "contact" phenomena was examined in eight animals with special efforts made to minimize any pressure effects that might be attend¬ ant with balloon placement. The re¬ sults are tabulated in the Table and an example graphically shown in Fig 1. The average reduction in the evoked potential due to eighth nerve manipulation (ie, placement of sili¬ cone sheeting, balloon contact, or both) was 29% with a SD of 14%. As shown in Fig 1, the effect was imme¬ diate and dramatic. From the Table it is seen that this reduction was not strictly due to pressure, since very gentle placement of pieces of silicone sheeting alone resulted in a substan¬ tial reduction of the evoked poten¬ tial (eg, 40%, 40%, and 38%). Further, since silicone is relatively inert and saline-moistened cotton alone in con¬ tact with eighth nerves resulted in evoked potential reduction, the phe¬ nomena is probably independent of the balloon material.
Fig 2.—More profound
Fig 3.—Complete
reduction in evoked
loss of evoked
potential
with second inflation of balloon.
potential with balloon inflation.
Amplitude Alterations The amplitude of the evoked poten¬ tial was found to be reduced con-
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 05/27/2015
evoked
potential with
inflation and potential with deflation. Additionally the phenom¬ ena as a function of time and eighth nerve manipulation is noted. The eighth nerve apparently became more susceptible to inflation; for as shown in Fig 2, a second inflation with the same volume as the first inflation re¬ sulted in a more profound reduction in evoked potential. Figures 2 and 3 also show that when inflation was great enough to abolish the evoked potential the return on deflation was slowed or there was no return at all. In many instances the amount of in¬ flation required to achieve a revers¬ ible reduction in evoked potential was limited. Beyond this point small addi¬ tional inflation completely and per¬ manently abolished the evoked poten¬ tial. Figure 4 illustrates a preparation where the balloon failed to maintain volume. After inflation there was a slow spontaneous deflation and a par¬ some
return in evoked
allel return in the evoked potential. However, with each inflation there was once again a substantial reduc¬ tion in the evoked potential.
In Fig 2 to 4 pure tones as well as clicks were used as auditory stimuli. No consistent differences in the evoked responses were noted between clicks and pure tones.
Fig 4.—Balloon
Latency
Alterations
With inflation the latency between auditory stimulation and onset of evoked potential was prolonged. The changes were not dramatic but con¬ sistent. In Fig 1 and 4 the reciprocal of the latency (in milliseconds) is plotted over amplitude alterations. It is apparent that prolongation of la¬ tency paralleled evoked potential re¬
duction. Further, with deflation and return of the evoked potential the la¬ tency returned toward normal. Two other observations were made. (1) The prolongation in latency did not occur with balloon contact. (2) It was not possible to show the latency change to be a continuous function of balloon inflation, rather latency changed in a stepwise fashion. There was either a moderate, but definite increase in the latency or total block¬ ade of neural transmission and there¬ fore no recordable latency alteration. COMMENT The finding of two foci of high-am¬ plitude evoked potential in auditory cortex AI is in agreement with the observations of other investigators." The base line values recorded for both latency and amplitude of evoked po¬ tential are also in agreement with the findings of other investigators."1" The figure given for the average re-
that failed to maintain Inflation
(see text).
duction in evoked potential due to "contact" and its standard deviation must be qualified since it is only accu¬ rate where their values were greater than zero. In some instances, no mat¬ ter how gentle, balloon placement abolished the evoked potential. If these instances are considered the average reduction and standard de¬ viation would of course be greater. Two observations suggest the distinctiveness of the "contact" phenom¬ ena from loss due to balloon inflation. (1) Even the most careful placement of silicone sheeting resulted in sub¬ stantial evoked potential reductions. (2) With "contact" there was no alter¬ ation in latency as seen with balloon inflation. This suggests that the evoked potential reduction due to con¬ tact is distinct from that due to bal¬ loon inflation since the latter is coupled to latency alterations and the former is not. In the Table it is seen that balloon placement over previously placed sili¬ cone sheeting results in an additional reduction in evoked potential of ap¬ proximately 5%. This additional re¬ duction is probably due to the pres¬ sure of the nerve attendant with balloon placement. "Contact" reduc¬ tion is negated by the interposed sili¬ cone sheeting. The magnitude of this additional evoked potential reduction is small in comparison to that ob¬ served with contact and with balloon inflation and, therefore, is not a ma¬ jor factor in evoked-potential altera¬ tions. The alterations in evoked potential observed in this study can be com¬ pared with observations from periph¬ eral nerve studies on the effect of compression on nerve function. In the early 1940s Weiss and Davis' studied the effects of compression on isolated rat sciatic nerves. They found that compression resulted in a rapid and progressive fall in action potential and that the effect was reversible on release of compression. Although the present study deals with a special sensory
nerve vs a
motor
nerve
(sci¬
is some evidence that motor and sensory nerves are differ¬ entially sensitive to compression,4 the basic effect on nerve conduction is the
atic) and there
same.
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Two other observations are perti¬ (1) There may be heightened nerve excitability as the initial re¬ sponse to nerve manipulation and to ischemia."; Perhaps the increase in evoked potential following balloon in¬ flation seen in Fig 1 to 3 can be ex¬ plained by such heightened nerve ex¬ citability. (2) Damaged nerve fibers are more susceptible to ischemia.11 Certainly, no matter how carefully performed there must be some ele¬ ment of eighth nerve injury in the preparation of these animals. In addi¬ tion, there is probably local ischemia associated with balloon inflation and, therefore, a more profound reduction in evoked potential would be expected with each subsequent balloon infla¬ tion. That this is the case is illus¬ trated by Fig 2 and 3. In Fig 2 the second inflation results in a greater reduction in evoked potential as well as a delayed (for 500 and 4,000 cps) and reduced return on deflation. In Fig 3 the amount of return with de¬ flation is reduced and there is a delay in return of the evoked potential to clicks. An additional observation made in this study relative to amplitude alter¬ ations was that in several prepara¬ tions even the most minor eighth nerve manipulation resulted in com¬ plete loss of the evoked potential. Al¬ though more often than not there was no return in evoked potential with nent.
deflation, this short-term study was limited by the six to ten hours the preparation remained physiological. Return of function after compression
injury to
nerves
may
require days
mals could then give the final behav¬ ioral correlates to these simulated
eighth
nerve
tumors.
or
weeks3 and would be missed in these short-term experiments. This increase in latency recorded in this study may be related to the dif¬ ferential effect that compression has on nerve fibers of differing size.1' Con¬ duction of the fastest impulses are in¬ terrupted before complete blockade.11 This would result in an apparent re¬ duced conduction velocity and prolon¬ gation in latency. Since a similar mechanism is probably the explana¬ tion for the amplitude alterations seen, the two functions would be ex¬ pected to parallel one another. That this is the case is shown in Fig 1 and 4 with amplitude plotted over the recip¬ rocal of latency. This is a preliminary study and much more is to be learned of the ba¬ sic pathophysiology of eighth nerve lesions using this animal model and its extension the long-term prepara¬ tion. The question of the contribution of vascular occlusion to auditory sys¬ tem function alteration could be ap¬ proached with perfusion studies in conjunction with electrophysiological studies in these preparations. Fur¬ ther, histopathological examination would be necessary to evaluate any ischemie alterations of inner ear even
anatomy. Auditory conditioned ani¬
"
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This study was supported by training grant No. 5T01 NS 05553, from the National Institute of Neurological Diseases and Stroke, the Na¬ tional Institutes of Health, and by grant No. NS08181 from the National Institutes of Health.
References 1. Pool JL, Pava AA: Acoustic Nerve Tumors: and Treatment. Springfield, Ill, Charles C Thomas Publishers, 1970. 2. Cushing H: Tumors of the Nervus Acusticus. Philadelphia, WB Saunders Co, 1971. 3. Gelfan S, Tarlov IM: Physiology of spinal cord, nerve root and peripheral nerve compression. Am J Physiol 184-85:217-229, 1956. 4. Sunderland S: Nerves and Nerve Injuries: Part II. Degeneration Regeneration; A Classification of Nerve Injury. Baltimore, Williams & Wilkins Co, 1968. 5. Weiss P, Davis H: Pressure block in nerves provided with arterial sleeves. J Neurophysiol 6:269-286, 1943. 6. Porter EL, Wharton PS: Irritability of mammalian nerve following ischemia. J Neurophysiol 12:109-116, 1949. 7. Denny-Brown D, Brenner C: Paralysis of nerve induced by direct pressure and by tourniquet. Arch Neurol Psychiatry 51:1-26, 1944. 8. Miller J, Ryan A: Effects of medial geniculate lesions on click-evoked potentials in the cat. Exp Neurol 39:103-111, 1973. 9. Hawkins JE Jr: Cortical responses to click stimulation. Am J Physiol 133:321-322, 1941. 10. Ades HW: Central auditory mechanisms, in Field J (ed): Neurophysiology. Washington, DC, American Physiological Society, 1959, vol 1, chapt 24. 11. Denny-Brown D, Brenner C: Lesions in peripheral nerve resulting from compression by spring clip. Arch Neurol Psychiatry 52:1-19, 1944.
Early Diagnosis
