and block tapping test). In addition, supratentorial hypoperfusion3 was always detected.
We propose that our patient’s cognitive deficits were
the consequence of his cerebellar lesion. Several studies showed that the posterior or superior cerebellum
may be involved in higher cognitive functions,1,2,8-10 but
few data are available about a cognitive role of the
anterior portion of the cerebellum. In frontal lobe lesions, PET scans usually show a contralateral cerebellar hypometabolism. Conversely, in some infratentorial
lesions, PET and SPECT scans showed hypometabolism/hypoperfusion in the contralateral cerebral hemisphere.1 This reciprocal effect can be anatomically
explained through the known cerebrocerebellar circuits. These consist in a feedforward loop, the corticoponto-cerebellar pathway, and a feedback loop, the
cerebello-thalamo-cortical pathway.1 In addition to its
main projections to the sensorimotor cortex, the feedback loop also projects to some associative areas.8 Most
neuropsychological deficits occurring in patients with
infratentorial lesion are explained by a diaschisis effect
resulting in a defective activation of these areas.
In our patient, despite the presence of important
cognitive abnormalities, we were not able to detect
any significant hypometabolism/hypoperfusion in supratentorial regions, indicating that no diaschisis effect occurred, at least in its typical form. Also, the
potential relative hypometabolism of a portion of his
cingulate cortex cannot explain the extent of the observed neuropsychological deficits. Further functional imaging studies are necessary to define how
lesions in different infratentorial areas of the cerebellum may alter functional connectivity between
brain regions involved in cognitive tasks.
This case provides evidence of a direct involve-

Midbrain deafness
with normal
brainstem auditory
evoked potentials

ment of the cerebellum in some cognitive functions,
agreeing with findings of cerebellar activation during
cognitive processing in normal subjects.9 A threshold
effect may explain the variable effect of infratentorial lesions on cognition. Thus, bilateral anterior lesions, as observed in our patient, may be required to
produce significant cognitive abnormalities.1,2
References
1. Daum I, Ackermann H. Neuropsychological abnormalities in
cerebellar syndromes—fact or fiction? International Review of
Neurobiology 1997;41:455– 471.
2. Neau JP, Arroyo-Anllo E, Bonnaud V, Ingrand P, Gil R. Neuropsychological disturbances in cerebellar infarcts. Acta Neurol Scand 2000;102:363–370.
3. Hoffmann M, Watts A. Cognitive dysfunction in isolated
brainstem stroke: a neuropsychological and SPECT study.
Journal of Stroke and Cerebrovasc Dis 1998;7:24 –31.
4. Signorini M, Paulesu E, Friston K, et al. Rapid assessment of
regional cerebral metabolic abnormalities in single subjects
with quantitative and non-quantitative [18F]FDG PET: A
clinical validation of statistical parametric mapping. Neuroimage 1999;9:63– 80.
5. Van Bogaert P, Massager N, Tugendhaft P, et al. Statistical
parametric mapping of regional glucose metabolism in mesial
temporal lobe epilepsy. Neuroimage 2000;12:129 –138.
6. Leber WR, Jenkins RL, Parsons OA. Recovery of visualspatial learning and memory in chronic alcoholics. J Clin Psychol 1981;37:192–197.
7. Adams KM, Gilman S, Koeppe RA, et al. Neuropsychological
deficits are correlated with frontal hypometabolism in
positron emission tomography studies of older alcoholic patients. Alcohol Clin Exp Res 1993;17:205–210.
8. Middleton FA, Strick PL. Anatomical evidence for cerebellar
and basal ganglia involvement in higher cognitive function.
Science 1994;266:458 – 461.
9. Middleton FA, Strick PL. Cerebellar output channels. International Review of Neurobiology 1997;41:61– 82.
10. Kim SG, Ugurbil K, Strick PL. Activation of a cerebellar output nucleus during cognitive processing. Science 1994;265:
949 –951.

Abstract—The authors report two cases of patients with word deafness. The
word deafness occurred after a head injury for the first patient and after an
arterio venous malformation embolization for the second patient. MRI demonstrated bilateral lesions of the inferior colliculi but brainstem auditoryevoked potentials (BAEP) were within normal limits. These cases
demonstrated that lesions involving the two inferior colliculi induced pure
word deafness but do not affect BAEP.
NEUROLOGY 2002;58:970 –973

E. Vitte, MD, PhD; F. Tankéré, MD; I. Bernat, MD; A. Zouaoui, MD, PhD; G. Lamas, MD; and J. Soudant, MD

Pure midbrain bilateral and roughly symmetric lesion
is a rare cause of total deafness. Because the auditory
pathway is composed of crossed and uncrossed fibers
From the ENT Department (Drs. Vitte, Tankéré, Bernat, Lamas, and
Soudant), Hôpital Pitié-Salpêtrière, and the Radiological Department (Dr.
Zouaoui), Hôpital Pitié-Salpêtrière, Paris, France.
Received April 25, 2001. Accepted in final form December 4, 2001.
Address correspondence and reprint requests to Dr. Elizabeth Vitte, Service
ORL (ENT Department), Hôpital Pitié-Salpêtrière, 83-91 Bld de l’Hôpital,
75013 Paris, France; e-mail: elizabeth.vitte@psl.ap-hp-hop-paris.fr
970

Copyright © 2002 by AAN Enterprises, Inc.

with multiple synapses in the brainstem and reach
through the auditory radiations and the auditory temporal cortex, this pathway needs to be totally disrupted
to induce a total deafness. We report two cases with bilateral symmetric lesions of the inferior colliculi. The patients had total deafness but their brainstem auditoryevoked potentials (BAEP) were within normal limits.
Case report. Case 1. A 57-year-old right-handed
woman was seen at the ENT department of Pitié-

Figure 1. (A) Case 1. Surface-recorded brainstem auditory-evoked potentials (BAEP) to 38 dB (right side) and 56 dB (left
side) normal hearing level (nHL) rarefaction clicks disclose waves I, III, and V. There was no increase of latencies of these
waves on either side. Wave V was well preserved, with threshold of stimulation at 30dB nHL on both sides. (B) Case 2.
Surface-recorded BAEP to 53 dB (right side) and 30 dB (left side). Wave V was well preserved, with threshold of stimulation at 40dB nHL on both sides.
Salpêtrière Hospital, Paris, 15 days after a head injury.
She was disoriented and could speak, read, and write, but
was unable to hear. There was no evidence of a thought
disorder. Her history included losing consciousness during
a motor vehicle accident induced by a high blood alcohol
level. Standard pure tone audiometry demonstrated a mild
bilateral sensorineural hearing loss of 38 dB for the right
side and 56 dB for the left side. Impedance-audiometry
revealed normal middle ear pressure and mobility bilaterally. The crossed and uncrossed stapedial reflexes were
well preserved bilaterally. The acoustic reflex threshold

was 100 dB hearing level for 500, 1000, 2000, and 4000 Hz,
suggesting that the middle and inner ear and the auditory
nerve were intact. Speech audiometry failed to reveal any
response. BAEP were normal (figure 1A). The absolute
latencies for waves I, II, and V and the interwave latencies
I-III and I-V were subjects at 70 dB on both sides. In so far
as objective audiometry was normal while subjective audiometry was abnormal, her deafness was considered to be
psychological. She was submitted to a cerebral MRI. A
lesion localized to the tectum of the mesencephalon and
involving the two inferior colliculi was found. This lesion

Figure 2. Case 1. MRI, axial T2-weighted sequence, lesion involving the tectum of the mesencephalon mostly on
the left side.

Figure 3. Case 2. MRI, axial flow attenuated inversion
recovery sequence, infarction of the tectum of the
mesencephalon.
March (2 of 2) 2002

NEUROLOGY 58

971

was hyperintense on T1- and T2-weighted sequences, suggesting a hemorrhage (figure 2). She was treated with
bolus of steroids (1 g in a 1-hour perfusion of isotonic
glucose) 3 times for the first week and once a month for 6
months. After 18 months, there was a recovery of the
speech discrimination, which allowed the patient to wear
hearing aids.
Case 2. A 52-year-old right-handed man was seen at
the ENT department of Pitié-Salpêtrière Hospital, Paris, 2
days after an embolization of a diencephalic arterio venous
malformation that had induced a venous infarction of the
two inferior colliculi. He had a mild bilateral sensorineural
hearing loss of 53 dB for the right side and 30 dB for the
left side. Impedance-audiometry revealed normal middle
ear pressure and mobility bilaterally. The crossed and uncrossed stapedial reflexes were normal (acoustic reflex
threshold: 100 dB for all the frequencies tested); the BAEP
were also normal (see figure 1B). No responses were recorded during the speech audiometry. MRI showed two
well-limited hyperintense lesions involving the two inferior
colliculi and suggesting an infarction (figure 3). The patient was treated with a protocol including perfusions of
steroids and an agonist of dopamine (Piribedil; Eutherupie, Nevilly, France) for 1 week, followed by oral treatment for 2 months. Three months later, the speech
discrimination was 100% bilaterally.

Discussion. The auditory pathway is composed of
four neuronal networks. After passing through the
external and middle ear, the sound reaches the inner
ear where sensory transduction occurs. There is a
tonotopy in the inner ear with fibers of the apex of
the cochlea primarily responsive to low-frequency
sounds. Hair cells of the cochlea are connected to
type I auditory nerve fibers representing 95% of all
nerve fibers. The auditory nerve enters the brainstem at the pontomedullary junction and each type I
fiber terminates by splitting in two branches, one for
each of the cochlea nuclei.1 These fibers ascend as
the lateral lemniscus in the brainstem. Fibers from
the dorsal cochlear nucleus are projecting to the contralateral inferior colliculus. Fibers from the ventral
cochlear nucleus have multiple bilateral projections
including the trapezoid body, the superior olivary
complex bilaterally, and both bilateral lemnisci and
the inferior colliculi. The projections from the inferior colliculi terminate in the medial geniculate body
and give rise to geniculate-temporal fibers (auditory
radiations) that end in lamina IV of the primary
auditory cortex (area 41, gyrus of Heschl).2 This cortex is surrounded by association cortices.
The blood supply of all of these pathways is coming from the vertebral-basilar system. Branches from
the posterior cerebral artery supply the inferior colliculi while branches coming from the middle cerebral artery supply the auditory cortex.
BEAP consist of 7 waves occurring within 10 milliseconds after the onset of the click stimuli. Wave I
reflects mainly activity in the auditory nerve, wave
III projections in the inferior olivary complex, and
wave V the contralateral lateral lemniscus terminat972

NEUROLOGY 58

March (2 of 2) 2002

ing in the inferior colliculus or the inferior colliculus
itself.3,4
The neural generators of BAEP in humans are not
completely known. Attempts to identify the anatomic
locations of neural generators of the human BAEP
based on the results of animal’s studies commonly
used in auditory experimentation have been difficult
because of the considerable differences between the
ascending auditory pathways in humans and
animals.
Correlations between CT lesion sites and selective
abolition of BAEP wave V or IV-V complex were
made with patients who had midbrain-pontine hemorrhages or tumors.5 Wave IV and V were consistently abolished by lesions involving the dorsolateral
tegmentum of the midbrain-pontine junction area
and the upper pons. These waves were not affected
by lesions involving the inferior colliculus. It has
been concluded that intact dorsolateral area of the
upper pons is a prerequisite for waves IV and V to
occur. Also, it as been suggested a medial auditory
extralemniscal pathway.6
In the inferior colliculi, neurons are filters for
sounds that require immediate action; neural processing is species-specific.7 Components with latencies in the range of peak V elicited by contralateral
click stimulation had their largest amplitudes when
recorded from the lateral brainstem at the level of
the trochlear nerve.4
Our two cases are examples of bilateral inferior
colliculus lesions and total clinical deafness but with
preservation of wave V on BAEP recordings. MRI
abnormalities provide objective anatomic evidence
for the organicity of the deafness. For the first case,
contusion along the posterolateral aspect of the midbrain after head injury might be because of direct
contusion by adjacent structures such as the free
edge of the cerebellar tentorium. The second case is
related to an infarction of the two inferior colliculi,
probably of iatrogenic venous origin.
If wave V was generated by the inferior colliculus,
our two patients should demonstrate a distortion or
an abolition of wave V, but even for the lower intensity, wave V developed constantly. To our knowledge,
three similar cases have been reported.8-10 This suggests that wave V is not generated by the inferior
colliculus but in a region caudal to the inferior colliculi and may be in the dorsolateral area of the
upper pons, which is consistent with the abolition of
waves IV and V in lesions affecting this area.
Acknowledgment
The authors thank Dr. Nadine Martin-Duverneuil for providing
figure 2.

References
1. Häusler R, Levine RA. Auditory dysfunction in stroke. Acta
Otolaryngol 2000;120:689 –703.
2. Diamond IT, Feldman M, Galambos R, Goldberg JM. Neuroanatomy of the auditory system: report on workshop. Arch
Otolaryngol Head Neck Surg 1973;98:397– 413.
3. Melcher J, Kiang N. Generators of the brainstem auditory

potentials in cat. III: Identified cell population. Hear Res
1996;93:52–71.
4. Moller AR, Jho HD, Yokoda M, Janetta PJ. Contribution from
crossed and uncrossed brainstem structures to the brainstem
auditory evoked potentials: a study in humans. Laryngoscope
1995;105:596 – 605.
5. Chu NS. Brainstem auditory evoked potentials: correlation
between CT midbrain-pontine lesion sites and abolition of
wave V or the IV-V complex. J Neurol Sci 1989;91:165–177.
6. Hinman CL, Buchwald JS. Depth evoked potential and single
unit correlates of vertex midlatency auditory evoked responses. Brain Res 1983;264:57– 67.
7. Casseday JH, Covey E. A neuroethological theory of the oper-

HLA-A2 homozygosity
but not heterozygosity
is associated with
Alzheimer disease

ation of the inferior colliculus. Brain Behav Evol 1996;47:311–
336.
8. Hu CJ, Chan KY, Lin TJ, Hsiao SH, Chang YM, Sung SM.
Traumatic brainstem deafness with normal brainstem auditory evoked potentials. Neurology 1997;48:1448 –1151.
9. Meyer B, Kral T, Zentner J. Pure tone deafness after resection
of a tectal plate glioma with preservation of wave V of brainstem auditory evoked potentials. J Neurol Neurosurg Psychiatry 1996;61:423– 424.
10. Masuda S, Takeuchi K, Tsuruoka H, Ukai K, Sakakura Y.
Word deafness after resection of a pineal body tumor in the
presence of normal wave latencies of the auditory brain stem
response. Ann Otol Rhinol Laryngol 2000;109:1107–1112.

Abstract—AD is associated with the A2 allele of the human leukocyte antigen (HLA). However, it is not currently known whether there is any difference between A2 homozygotes and A2 heterozygotes. The authors studied 458
patients with AD and found that A2 homozygotes had earlier onset of AD
than either A2 heterozygotes (5.4 years, p ⫽ 0.002) or those without A2 (5.2
years, p ⫽ 0.003). The “recessive” nature of this association suggests that loss
of function at the HLA-A locus or a closely linked gene is associated with AD.
NEUROLOGY 2002;58:973–975

S. Zareparsi, PhD; D.M. James, BS; J.A. Kaye, MD; T.D. Bird, MD; G.D. Schellenberg, PhD; and
H. Payami, PhD

AD, the most common neurodegenerative disorder, is
genetically heterogeneous. The common form of AD,
which includes sporadic early-onset AD and lateonset AD, is associated with the apolipoprotein E
(APOE) gene.1 APOE-â‘€4 allele is associated with increased risk and earlier onset of AD, whereas
APOE-â‘€2 allele is associated with decreased risk and
delayed onset. However, APOE-â‘€4 is neither sufficient nor necessary for development of AD. Additional genes are suspected to contribute to the
development of AD. Thus, many studies have examined the role of various genes on AD susceptibility.
Several studies have reported an increased frequency of human leukocyte antigen (HLA)-A2 allele
in patients with early-onset AD (reviewed by Payami
et al.2 and Harris et al.3). A recent meta-analysis
reported that the presence of one or more HLA-A2

alleles is associated with a modest increase in risk
for developing AD.3 Furthermore, one study examined the effect of HLA-A2 allele on age at onset of
AD.4 They observed that patients with AD with an
HLA-A2 allele had an average 3 years earlier onset
of AD than patients without A2. The association between the HLA-A2 allele and earlier onset of AD was
confirmed by subsequent studies in Spain and Italy.5,6 In addition, evidence for linkage to two regions
on chromosome 6 has been detected in a genome
scan of late-onset families.7 However, the question of
HLA-A2 allele dosage and a possible deferential effect of A2 homozygosity compared with A2 heterozygosity has not been addressed. Thus, the goal of this
study was to investigate the effect of HLA-A2 dosage
on age at onset of AD in a sample of 458 unrelated
patients with AD.

From the Department of Neurology (Drs. Zareparsi, Kaye, and Payami, and
D.M. James), Oregon Health Sciences University; Portland Veterans Affairs
Medical Center (Dr. Kaye) Portland, OR; Department of Neurology (Drs.
Bird and Schellenberg), and Department of Medicine and Pharmacology
(Dr. Schellenberg), University of Washington; Veterans Affairs Puget
Sound Health Care System (Drs. Bird and Schellenberg), Seattle, WA.
Supported by the Indiana Alzheimer Disease Center National Cell Repository, NIAA grant #P30 AG 10133, and by grants from the Alzheimer’s
Research Alliance of Oregon, Alzheimer’s Association (RG1-96-042), National Institute on Aging (AG-08017), Seattle Veterans Affairs Geriatric
Research Education and Clinical Center, and University of Washington
Alzheimer’s Disease Research Center (NIA-AG05136).
Received October 25, 2001. Accepted in final form December 4, 2001.
Address correspondence and reprint requests to Dr. Sepideh Zareparsi,
Oregon Health Sciences University, 3181 SW Sam Jackson Park Road,
CR-131, Portland, OR 97201; e-mail: zarepars@ohsu.edu

Patients and methods. This study was composed of 458
unrelated patients with AD (255 women and 203 men). All
patients received the clinical diagnosis of probable AD or
the neuropathologic diagnosis of definite AD as described
previously.4 Informed consent was obtained from every
subject or from their legal guardian. Positive family history was defined as having a first-degree relative with AD
or progressive memory loss (familial AD ⫽ 330, sporadic
AD ⫽ 113, unknown family history ⫽ 15). Age at onset was
defined as the age when memory loss was first noticed by
relatives. Mean onset age (⫾SD) was 68.0 ⫾ 10.1 years.
HLA-A genotypes were obtained using a commercially
available kit, the Olerup SSP HLA-A SSP Combi Tray
(GenoVision, West Chester, PA). APOE genotypes were
Copyright © 2002 by AAN Enterprises, Inc.

973

Midbrain deafness with normal brainstem auditory evoked potentials
E. Vitte, F. Tankéré, I. Bernat, et al.
Neurology 2002;58;970-973
DOI 10.1212/WNL.58.6.970
This information is current as of March 26, 2002
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