Brainstem Auditory Evoke.d Responses in Infants and Children with AIDS Yitzchgk Frank, MD*+, S. Murthy Vishnubhakat, MD*, and Savita Pahwa, MDT

Brainstem auditory evoked responses were measured in 16 infants and children with acquired immunodeficiency syndrome (AIDS) and in 9 normal infants and children. Two stimulation rates were used: a conventional rate of 10 Hz and a high rate of 50 Hz. Latencies of waves III, IV, and V on the left were significantly longer in the AIDS group when a stimulation rate of 10 Hz was used. With a higher stimulation rate of 50 Hz, significant differences between the two groups occurred in the latencies of waves I, III, and V bilaterally, but there were no significant differences in the interpeak latencies..A measure of the differential effect of the increasing stimulus rate on the two groups was significant for wave I latency and for I-III and I-V interpeak latencies on the left, revealing that increasing stimulation rate prolongs these measures more in the AIDS group. Increased brainstem auditory evoked response stimulation rate may unmask abnormalities in infants and children with AIDS that are not observed when the lower stimulation rate is used.

Frank Y, Vishnubhakat SM, Pahwa S. Brainstem auditory evoked responses in infants and children with AIDS. Pediatr Neurol 1992;8:262-6.

Introduction

The nervous system is commonly affected in adult acquired imrnunodeficiency syndrome (ADS), either directly by the human immunodeficiency virus (HIV) or by secondary infections. The developing central nervous systein can also be affected in the disease, but there is little knowledge about the natural history and pattern of progression of the neurologic manifestations of the disease in infants and children. Similarly, the role of various laboratory tools in diagnosis and monitoring of the pediatric nervous system affected by AIDS is not known. Brainstem auditory evoked responses (BAERs) are a series of waves originating in the auditory nerve and in the brainstem during the first 10 ms following auditory stimuli. The wave and interpeak latencies reflect the response conduction in the central auditory pathway and, therefore, Fromthe Departmentsof *Neurologyand+Pediatics;North Shore. UniversityHospital;CornellUniversity;MedicalCollege;Manhasset, New York.

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PEDIATRICNEUROLOGY Vol. 8 No. 4

can serve as indicators of the integrity or disruption of the central neurologic pathways. Neurologic disease causing brainstem pathology or central demyelination (i.e., hypoxic-ischemic encephalopathy, trauma, leukodystrophy,

Leigh disease) can cause BAER abnormalities in wave or interpeak latencies or wave amplitude [ l-51. When the stimulus rate is increased, the latency of all BAER waves increases, along with decreased amplitude and recognizability [6,7]. The effect of increasing stimulus rate on BAER latencies can be calculated by subtracting wave or interpeak latencies obtained at a low stimulus rate (i.e., 10 Hz) from the corresponding latencies obtained when a higher stimulus rate (i.e., 50 Hz) is used [8]. Several studies demonstrated that BAER abnormalities in myelin disorders, head trauma, and hypoxic encephalopathy can be “unmasked” by increasing the stimulus rate [3,9]. In this study, we compared latencies of BAER wave and interpeak latency recorded in infants and children with AIDS, with those of a control group of normal infants and children, using a standard and a high stimulation rate (10 Hz id 50 Hz, respectively). Methods There were 16 children with AIDS and 9 normal control infants and children. All had neurologic involvemenb mostly in the form of developmental abnormalities in motor and language &as. All had normal hearing and were not on antiviral medications. The age of the pediatric control group was 9.0 years with S.D. 4.5 (range: 5 months to 14 years), while the average age of the AIDS patients was lower, 4.1, with S.D. 3.1 (range: 6 months lo 11 years). There is a clear developmental pattern of BAER parameters. All wave and interpeak latencies are longer in neonates and young infants and the more rostral waves have a longer developmental course [IO]. Wave V latency reaches adult values by 12-18 months of age [I 11. The relationshipbetweenthe stimulus rate and the response latencyalsomay

be more pronouncedin neonatesand very younginfantsthan in adults [10,12,13], but this difference. is probably not significant beyond 1 year of age; therefore, when the population examined is older than 18 months, adult norms probably can be used. Although there is a difference .between the mean age of the groups, BAER latencies and the latency differences resulting from using higher and lower stimulus rates can be compared.

BAERs were elicited and measuredby. a Neuroscope(Giegen) evokedpotentialsaverager.The stimuli were monaural, filtered, 80 dB clicksof alternatepolarity,100micmsecin duration,deliveredthrough headphonesat a rate of 10 Hz and 50 Hz. The other ear wasmasked. Communications shouldbe addressed to: Dr. Frank,Departmentof Neurology;Divisionof PediatricNeurology; North ShoreUniversityHospital;300CommunityDrive; Manhasset,NY 11030. ReceivedFebruary14. 1992;acceptedMay 28, 1992.

Table

1.

BAER:

Wave

and interpeak

latencies

in 9 normal

pediatric

controls

Mean L lo/Hz

SD.

Mean L so/Hz

S.D.

Mean R lo/Hz

S.D.

Mean R SO/Hz

S.D.

I

1.381

0.095

I.393

0.175

I.461

0.207

I .526

0.195

II

2.503

0.328

2.694

0.265

2.639

0.285

2.697

0.275

III

3.529

0.299

3.778

0.313

3.620

0.347

3.804

0.369

IV

4.567

0.238

5.044

0.105

4.694

0.274

4.910

0.318

V

5.520

0.561

5.857

0.502

5.538

0.354

5.841

0.482

I-III

2.148

0.245

2.384

0.433

2.159

0.303

2.279

0.343

III-V

1.991

0.272

2.079

0.247

1.918

0.103

2.037

0.160

I-V

4.139

0.503

4.463

0.623

4.077

0.288

4.316

0.468

Wave

Abbreviations L = Left ear R = Right ear

Potentials were recorded from the vertex (Cz) with reference to the ipsilateral ear and the contralateral earlobe acting as ground. Filter range was 150-3,000 Hz and analysis time was 10 ms. Two stimulation rates were used, 10 Hz and 50 Hz. Responses to 2,000 stimuli to each ear were averaged IO produce each trace and a duplicate of each average was made to assess reproducibility. The averaged potentials were displayed on a screen and the Iatencies of waves I-V and interpeak latencies I-111, III-V and I-V were scored. A paper tracing was then obtained. The additional measurements calculated were the differences between wave I, III. and V latencies and interpeak latencies I-111, III-V, and I-V obtained with both stimulation rates 10 Hz and 50 Hz. Statistical analysis of the data included an analysis of variance, using the Kruskal Wallis test (chi square approximation), to assess the significance of the differences of the BARR wave and interwave latencies between the AIDS and control groups, and the significance of the differences obtained by stimulation rates 10 Hz and 50 Hz.

and also were usually longer in the AIDS group when compared with the normal group (Tables l-2; Figs l-3). Wave-shape was only minimally affected by increasing stimulation rate in the controls (Fig l), but more affected in the AIDS patients (Figs 2,3). Comparing the two groups for peak and inter-peak latencies obtained with a stimulus rate of 10 Hz demonstrated significantly longer latencies (P c .05) of waves III, IV, and V on the left in the AIDS group. Increasing the stimulus frequency to 50 Hz elicited significant differences between the two groups in the latencies of waves I, III, and V bilaterally, but not in the interpeak latencies (Table 3). When the differences between the peak and interpeak latencies obtained with both stimulation frequencies 10 Hz and 50 Hz were compared between the AIDS and the control groups, significant differences were found in wave I latency (P < .OOS),I-III inter-peak latency (P c .02), and I-V interpeak latency (PC .05), all on the left (Table 4).

Results seak and inter-peak latencies in both groups were usually longer when the higher stimulation rate of 50 Hz was used Table

2.

BAER:

Wave

and interpeak

latencies

in 16 pediatric

AIDS

patients

SD.

MeZUl R 50&

Mean SD.

I .605

0.320

1.823

0.349

0.227

2.711

0.361

2.939

0.511

4.349

0.630

3.816

0.409

4.143

0.726

0.328

5.278

0.481

4.879

0.416

4.975

0.606

5.825

0.606

6.338

0.748

5.761

0.391

6.306

0.512

I-III

2.276

0.331

2.266

0.445

2.192

0.280

2.382

0.528

III-V

1.928

0.388

2.131

0.384

1.945

0.260

2.144

0.605

I-V

4.208

0.419

4.252

0.541

4.148

0.393

4.428

0.513

Mean L lOA37,

S.D.

Mean L 5on32

SD.

I

1.509

0.201

1.920

0.443

II

2.684

0.307

2.903

III

3.859

0.544

Iv

4.955

V

Wave

Mean R lo/Hz

Abbreviations: L = Left ear R = Rightear

FraolcetabBAERidAIDS

263

1

I

III A

B C D I I

I

I

I

I

I

0

2

4

6

8

10

ms (A,B) Leji ear stimulaFigure 1. BARR of a 3-year-old normal boy. tion rate of 10 Hz and 50 Hz, respectively. (CD) Right ear stimuiation rate of 10 Hz and 50 Hz, respectively. Wave-shape is not signijicandy changed and larencies are slightly prolonged on the lefr but not on the right with the high stimulation rate. Latencies for 10 Hz stimulation rate: Left: 1:1.3, III:3.6, V:5.4, i-11/:2.3, III-V:I.8, and I-V:4.I ms; Right: I:I.4. [II:3.8, V:5.7, I-111:2.4. III-V:I.9, and I-V:4.3 ms. Latencies for 50 Hz stimulation rate: Lefr: I:1.4, 111-3.7, V:5.8, IIII:2.3, III-V:2. I, and I-V:4.4 ms. Right: I:I.3, III:3.4. V:5.3. I-111:2.1. III-V:l.9, and I-V:4.0 ms. Amplitude calibration: I.0 pV/division.

inter-peak latencies of the two groups. Nevertheless, when the differences between the wave and interwave latencies obtained with both 10 Hz and 50 Hz were computed, in order to assessthe differential effect of increasing stimulus rate on the two groups, significant differences between the groups were demonstrated for interpeak latencies III-I and V-I on the left, as well as for wave I on the left, meaning that a higher stimulation rate of 50 Hz increased latencies in the AIDS group more than in the pediatric control group for those measures. When the stimulation rate was increased to 50 Hz, significant differences between the AIDS and control groups occurred in the latencies of the major peaks I, III, and V, but ‘not in interpeak latencies, suggesting that the higher stimulation rate causes the latencies of all 3 waves to be about equally prolonged. Such a pattern of abnormality suggests a neuronal or synaptic dysfunction more than a

VIY-+--A z-

Discussion Our study demonstrates that brainstem conduction, as manifested by some BARR latencies, is longer in infants and children with AIDS compared to controls. Increasing the stimulation rate to 50 Hz increased the number of differences between the AIDS group and normal children, but there still were no significant differences between the

I

III

V

\/lo, III

I

III

V

C

TD

1 2

4

6

8

10

ms

V

VA I

I

97

0 III

I3

.->

V

Figure 3. BARR of a lo-year-old girl with AIDS dementia and spasticity. (A,B) L.ej ear stimulation rate of 10 Hz and 50 Hz, respectively. (CD) Right ear stimulation rate of 10 Hz and 50 Hz. respectively. With a high stimulation rate of 50 Hz there is a markedly abnormal wave-shape on the lefr composed of 2 broad peaks that cannot be scored. Some peaks can be seen on the right, but are of a low voltage and cannot be clearly identified. Lotencies for IO Hz stimulation rate: Lej I: 1.6, III:3.9, V:6,2, I-111:2.3. III-V:2.3. and I-V:4.6 ms. Right: I:l. 7, III:3.8. V:6. I. I-111:2. I, III-V:2.3. and I-V:4.4 ms.

-C hD

Figure 2. BARR of a 4!4-year-old girl with AIDS, increased deep tendon reflexes in the lower extremities, abnormal gait, and dij%se cognitive abnormalities. (A,B) Lq? ear stimulation rate of IO Hz and 50 Hz respectively. (CD) Right ear stimulation rate of 10 Hz and 50 Hz, respectively. Latencies are prolonged with the higher stimulation rate. Wave-shape is less distinct with the higher stimulation rate on the lefr and cannot be identified on the right. Latencies for 10 Hz stimulation rate: Left: I:1.7, III:4.1, V.6.0, I-111:2.4, III-V:1.9, and IV:4.3 ms. Right: I:2.1, III:4.3, V.6.3. I-111:2.2, III-V:2.0, and I-V:4.2 ms. Latencies for 50 Hz stimulation: Lefi: I:2.4, III:4.6. V6.6, lIII:2.2. III-V:2.0, and I-V:4.2 ms. Right: no clear response.

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PEDIATRIC

NEUROLOGY

Vol. 8 No. 4

central demyelinating process, as the possible etiology of brainstem abnormalities in infants and children with AIDS. When the effect of increasing the stimulation rate in the two groups is quantitatively compared, differences are found in some latency measures, but not in others. The lack of a uniform effect may be due to the fact that our patients were in different stages of the disease and such an effect is present in some, but not in all. It is also possible that the disease affects various parts of the brainstem unequally. Last, a nonuniform effect may be due to lack of statistical power because of a small number of patients. Studies of BARR in HIV seropositive men without AIDS revealed prolonged wave V and I-V interpeak latenties compared with controls [14-161. There are very few reports of electrophysiologic abnormalities in children

Table 3. BAER: latencies between

Analysis of variance of wave and interwave the AIDS and control groups*

L lo/Hz

L so/Hz

R lo/Hz

R SO/Hz

I

0.0705

0.0014+

0.2295

0.0152+

II

0.0623

0.0935

0.5703

0.2502

III

0.0186+

0.0047+

0.1317

0.0505+

IV

0.0045+

0.2502

0.2984

0.7411

V

0.0455+

0.0164+

0.0624

0.0222+

I-III

0.1616

0.8580

0.6526

0.5906

III-V

0.8906

0.8203

0.8458

0.8168

I-V

0.1618

0.9734

0.3091

0.2689

Wave

* The probability is greater than chi square. + P c .05, Kruskal Wallis test (chi square approximation).

with AIDS. Prolonged I-V interpeak latencies or an abnormal response to an increased rate of stimulation was demonstrated by BAERs in 4 of 5 children tested [ 171. Shortening of BAER I-V interpeak latency was reported in a young infant 6 and 12 months after AZT therapy [ 181. No abnormalities were disclosed in 16 of 29 children with early stages of the disease [19]. Pratt et al. reported that increasing the rate of stimulation to 50 Hz improved the yield of detection of BAER abnormalities [9]. In another study, BAER abnormalities were found in 24% of patients with chronic renal failure undergoing hemodialysis when the stimulation rate of 10 Hz was used and in 44% of them when the rate was increased to 55 Hz [8]. Hecox and Burkard reported that 4% of their patients with central auditory pathology, mostly patients with multiple sclerosis and closed-head injury, exhibited abnormalities only at a higher stimulation rate [IO]. Abnormally increased wave V latency in response to an increasing stimulus rate from 20 Hz to 90 Hz was demonTable 4. Analysis of variance of wave and interwave latency differences (SO/Hz minus latency lo/Hz) between the AIDS and control groups Left

Ear

Right

Ear

Wave I

O.OOSO*

0.1867

Wave III

0.9999

0.47 I.5

Wave V

0.9356

0.4170

0.0157*

0.5712

0.4966

0.7576

o.O4ss*

0.0928

Interpeak latency

1-m

Interpeak latency

lB-V

Interpeak latency

I-V

* P c .05, Kruskal

WalIis

test (chi square approximation).

strated in children with neurologic abnormalities, mainly following hypoxic-ischemic episodes in the prenatal or neonatal period [20]. Still, the diagnostic value of the use of a high stimulation rate is controversial [7]. When a group of patients with multiple sclerosis was tested using a stimulus rate of 10 and 70 Hz, the increased stimulation rate did not detect abnormalities in patients who were normal with the lower stimulation rate; however, abnormalities observed at 10 Hz were sometimes worse at the faster rate [21]. Don et al. discussed the effects of increasing BAER stimulus rate on the detection of abnormalities [6]. Sensory systems, including the auditory pathway, require a period of time to recover fully the ability to respond following the stimulus. If a subsequent stimulus were to occur before complete recovery, the response may be altered. Increased latency as a result of an increased stimulus rate probably is a sign of incomplete recovery. If central conduction were impaired, as in conditions causing demyelination, abnormal synaptic transmission, receptor abnormalities, or desynchronization of the different components giving rise to the response, the refractory period may be such that a response would be delayed or could not be obtained at the higher rate because of incomplete recovery [22]. In the presence of brain pathology, the auditory pathways may have more difficulties in conducting neural impulses at a higher stimulus rate [20]. It is possible, tberefore, that early central nervous system abnormalities in children with AIDS, manifested as abnormally increased BAER latencies, will be detected when a higher stimulation rate of 50 Hz or more is used. We are grateful to Jessica Seiden, Valerie MaIerba, and Marsha Riegel, MS for technical assistance, and to the Division of Biostatistics at North Shore University Hospital for performing the statistical analysis. This study was partially supported tional Institute of Drug Abuse.

by Grant

(DA05161)

from The Na-

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