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Auditory brainstem responses in Friedreich's ataxia.

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Philip A. Schwartzkroin, PhD
Dr Prince confuses three separate issues in his comments on
our paper about intracellular recordings from human and
The first question is whether
monkey “epileptic” cortex [4].
the in vitro slice preparation is adequate for investigating
the cellular mechanisms underlying epileptogenesis. My colleagues and I believe that this in vitro approach has considerable potential, and we continue to carry out such studies;
indeed, we have collected interesting new data which will be
reported soon.
The second question is whether current results from in
vitro studies of human tissue provide convincing data on differences between epileptic and normal cortex. Conservative
interpretation of available intracellular data does not allow
one to identify cortical slices as “epileptic” or “normal.” In
our paper [4],we clearly indicated that controls were inadequate, and we therefore made no claim as to the epileptogenicity of any given tissue sample. The point is not that our
controls were better than those of Prince and Wong 12) but
rather that neither study had adequate controls. From this
perspective, therefore, the Prince and Wong interpretation
was premature. Since there is evidence that much of cortex
may be abnormal in epileptic brain 111, why should one assume that cortex in brain with other abnormalities but without electrocorticographical spikes (i.e., the Prince and Wong
“control” cortex) is normal? And what are the normative data
that allow a comparison of epileptic temporal cortex and
normal frontal or parietal cortex? While I was at Stanford, I
personally carried out some of the electrophysiological human slice studies subsequently reported by Prince and Wong
121. O n the basis of those four or five experiments, no distinction could be made between epileptic and normal cortex.
It is, of course, possible that additional studies and sophisticated data analysis could reveal trends and differences not
obvious from these initial experiments, but the specific analyses that led to Prince and Wong’s more “optimistic” interpretations were not explained [2). W e do not maintain that
differences do not exist between tissue slices from epileptic
and normal brain; rather, we maintain that the available data
have not convincingiy shown those differences.
The third point raised in Dr Prince’s comments deals with
characteristics of epileptic neurons. Prince apparently associates the all-or-none burst shown in his Figures 1 and 2 [2)
with epileptiform activity. I t is unclear, however, how many
such bursting neurons were observed in their “epileptic” cortex. The cellular bursts were apparently not associated with a
population discharge. If this is so, how can the occurrence of
an isolated neuronal event be characterized as “epileptiform”
when epilepsy may well be a population phenomenon? The
burst discharge shown by Prince and Wong might be an
epileptiform PDS burst, or might simply be the discharge
pattern of a normal cell in temporal lobe; the data do not
provide a basis for deciding which.
Regarding the apparently normal appearance of intracelluPrince seems to imply
larly stained neurons in our study [4],
that those ceils were not in the epileptic focus. Such an interpretation is somewhat tricky because it is precisely the
definition of the term focus that needs clarification. If the
determination of a focus can be made strictly on the basis of
electrocorticographical “spikes,” then our apparently normid
neurons were within the focus. We are not satisfied with this
sole criterion, for ifforus were so simply defined, the success
rate for neurosurgical “cures” would be much higher. Studies
on characterizing a focus [ l ) have shown that the problem is
complex and still unresolved. We are also unsure that the
morphologically abnormal neurons, which have been demonstrated in chronic foci [ S } , are the same cells that are “hyperexcitable”; perhaps those morphologically abnormal cells
are too sick to discharge repeatedly, and cells with more
subtle changes maintain the epileptiform activity.
D r Prince’s reaction to our paper is somewhat puzzling, for
it seems clear that the published data from in vitro slice studies of human cortex cannot support an interpretation of tissue
epileptogenicity. The preparation may provide a unique 011portunity to investigate cellular mechanisms 131, but to do c,o
with human neurons in tissue taken from human epileptic
brain does not guarantee our ability to elucidate cel1ul;;lr
mechanisms of epileptogenesis. Interpretation of the data
should be cautious and based on the same rigorous standards
used to interpret results from any other intraccllular study.
Department of Neurological Srirgeq
University of Washington
Seattie. W A 981 95
References
1. Engel J Jr, Kuhl DE, Phelps ME, Crandall PH: Comparative hcalization of epileptic foci in partial epilepsy by PCT and E E G
Ann Neurol 12:529-537, 1982
2. Prince DA, Wong RKS: Human epileptic neurons studiecl in
vitro. Brain Res 210:323-333, 1981
3 . Schwartzkroin PA, Prince DA: Microphysiology of humarr cerebral cortex studied in vitro. Brlun Res 115:497-500, 197C
4. Schwartzkroin PA, Turner DA, Kiiowles WD, Wyler AR: Studies of human and monkey “epileptic” neocortex in the in vitro
slice preparation. Ann Neurol 13:249-2j7, 1983
5. Westrum LE,White LE Jr, Ward AA J r . Morphology of the
experimental epileptic focus. J Neurosurg 2 1.1033-1046, lY14
Auditory Brainstem
Responses in
Friedreich’s Ataxia
Margot J. Taylor, PhD
In a recent article Nuwer and collcagues [21 reported normal
auditory brainstem responses (ABRs) in up to 20 patients
with Friedreich‘s ataxia. This is at variance with several recent
reports in the literature [3-6). We have found normal ABRs
only in very young patients with Friedreich’s ataxia; we also
found that abnormalities increase with the duration of the
disorder [b]. In contrast to the suggestion of Nuwer and
colleagues, the ABR abnormalities were not a function of
peripheral hearing problems, as all but L of our patients had
normal audiometric examinations. In a second, current seriies
of 14 children and young adults with Friedreich’s ataxia, we
596 Annals of Neurology Vol 14 No 5 November 1983
consistently find progressive loss of the waves of the ABR in
children who had symptoms for more than a few years, resulting in a loss of the waveform in older patients.
A reason for the discrepancies between our data and those
of Nuwer and colleagues may he the criteria used to select
the patients. W e adhere to the criteria of the Quebec
Cooperative Study [I]. Another factor may be age; Nuwer
and colleagues did not give the ages of the patients with
Friedreich‘s ataxia. If they were very young it is possible that
ABRs would be normal. In our present series of patients
ranging in age from 5 to 21 years, only one, aged 6% years,
had normal ABRs. Only 28 of Nuwer’s 45 patients with
inherited ataxias received ABR testing, and there is no indication how many of these had Friedreich‘s ataxia.
Hospital for Sick Children
555 University Avenne
Toronto. Ont, Canada M5G 1 X 8
References
1. Geoffroy G, Barbeau A, Breton G, et al: Clinical description and
roentgenologic evaluation of patients with Friedreich’s ataxia. Can
J Neurol Sci 3:279-286, 1976
2. Nuwer MC, Perlman SL, Packwood JW, Kark RAP: Evoked potential abnormalities in the various inherited ataxias. Ann Neurol
13:20-27, 1983
3. Pedersen L, Trojaborg W: Visual, auditory and somatosensory
pathway involvement in hereditary cerebellar ataxia, Friedreich’s
ataxia and familial spastic paraplegia. Electroencephalogr Clin
Neurophysiol 52:283-297, 1981
4. Satya-Murti S, Cacace A, Hanson P Auditory dysfunction in
Friedreich‘s ataxia: result of spinal ganglion degeneration. Neurology ( N Y ) 30:1047-1053, 1980
5 . Shanon E, Himelfarb MZ, Gold S: Auditory function in
Friedreich‘s ataxia: Electrophysiologic study of a family. Arch
Otolaryngol 107:254-256, 1981
6. Taylor MJ, McMenamin JB, Andermann E, Watters GV: Electrophysiological investigation of the auditory system in Friedreich’s
ataxia. Can J Neurol Sci 9131-135, 1982
tive Study obligatory criteria. Our techniques are also similar.
Perhaps the patients studied by Taylor and colleagues represent a subset of Friedreich’s ataxia in whom BAEP changes
are particularly early and prominent. That most Quebec patients do represent a special, homogeneous subset has been
suggested before { l , 31.
We have recently seen two cases of abnormal BAEPs in
patients with Friedreich’s ataxia, including one 25-year-old
man with absent potentials bilaterally. In all, we have seen an
absent wave V in 1 of 8 patients. This is similar t o the ratio of
1 of 6 patients reported by Pedersen and Trojaborg. I n contrast, Taylor and colleagues reported an absent wave V in 13
of 16 patients.
We have always agreed that some patients with Friedreich’s
ataxia have abnormal or even absent BAEPs. O n the other
hand, our data show 6 patients with definitely normal
BAEPs. In our article we suggested, “BAEPs can he present
and often normal.” W e would now rather say, “BAEPs can be
present and sometimes normal in Friedreich’s ataxia.” The
rate of abnormality can be increased by using fast rates of
stimulation [2, 41.
Finally, the family reported by Shanon and colleagues [ 4 ]
has an autosomal dominant type of inherited ataxia. We are
not given enough data to determine if these patients have
Friedreich’s ataxia.
Department of Neurology
Reed Nezuological Research Center
710 Westwood Plaza
Los Angeles, C A
“Presentaddress:
Veterans Administration Hospital
5 10 East Stoner Ave
Shreveport, LA 71 130
References
1. Bouchard JP, Barbeau A, Bouchard R, et d:A cluster of Friedreich’s ataxia in Rimouski, Quebec. Can J Neurol Sci h:205-208,
1979
Reply
Marc R. Nuwer, MD, PhD, Susan L. Perlman, MD,
James W. Packwood, PhD, and R. A. Pieter Kark, MD”
Our 6 patients with Friedreich’s ataxia who underwent brainstem auditory evoked potential (BAEP) testing had a median
age of 20 years and disease duration of 11 years, similar to the
patients studied by Taylor and colleagues. The criteria for our
group were even more strict than the 1976 Quebec Coopera-
2. Brenner RP, Smith MWF, Aguilera AJ: Abnormal BAEPs in
Friedreich’s ataxia. Presented at the Central Assoc of Electroencephalographers, Indianapolis, March 26, 1381. Electroencephalogr Clin Neurophysiol, in press
3. Harding AE: Friedreich’s ataxia: a clinical and genetic study of 90
families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104:589-620, 198 1
4. Shanon E, Himelfarb MZ, Gold S: Auditory function in Friedreich’s ataxia: electrophysiologic study of a family. Arch Otolaryngo1 107:254-256, I981
Notes and Letters
597
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