ARTICLE
Auteur(s) : Kenan
Aydogan1, Omer Faruk Turan2, Selcuk
Onart3, Bulent Yazici4, Serap Koran
Karadogan5, Necdet Tokgoz1
1Department of Dermatology, Uludag University,
Faculty of Medicine 16059 Görükle, Bursa-Turkey
2Department of Neurology, Uludag University, Faculty of
Medicine, Bursa-Turkey
3Department of Otolaryngology Head and Neck Surgery,
Uludag University, Faculty of Medicine, Bursa-Turkey
4Department of Ophthalmology, Uludag University, Faculty
of Medicine, Bursa-Turkey
5Esrefpasa State Hospital, Izmir-Turkey
accepté le 24 Juin 2008
Isotretinoin (13-cis-retinoic acid, 13-cRA) is a retinoid that
has been used over the past two decades to treat a wide variety of
dermatological conditions. 13-cRA may, however, cause adverse
reactions on mucosa, skin, eye, liver, bone and the musculoskeletal
system [1, 2]. Adverse reactions involving the central nervous
system (CNS) which are definitely or probably related to oral
isotretinoin use include benign intracranial hypertension
(manifested as headache, papilloedema and cranial nerve palsies),
depression and disulfram-like reaction, insomnia, oculogyric
crisis, personality disorder and also decreased hearing [1-3].
Recent accumulating evidence indicates that synthetic retinoids may
be capable of affecting both the growth and differentiation of
nervous tissue in vivo and in vitro [4-7].
Adverse reactions concomitant with CNS/brainstem involvement
probably related to oral retinoid therapy have been reported in a
small number of patients [3, 8-11]. However, it seems possible that
the CNS toxicity of retinoids at the subclinical level may occur
more frequently than clinically evident adverse reactions.
Blepharoconjunctivitis, meibomitis, dry eye symptoms, contact lens
intolerance, blurred vision, photodermatitis of the eyelids,
corneal opacities, decreased visual acuity, abnormalities visual
field and retinal functions and papiledema have been reported
during systemic isotretinoin treatment [12]. Although it is
beneficial in many skin conditions, the side-effects and toxicity
of oral retinoids require careful monitoring by an experienced
physician.
Evoked potentials (EPs) are useful and sensitive tools for
investigating the function state of sensory pathways from the
periphery to the CNS. In clinical neuropharmacology, abnormalities
in EPs have also been shown to provide a sensitive index for the
detection and quantification of the neurotoxicity of several
compounds, also in the preclinical stages of disease [13].
The objective of this prospective study was to investigate
whether oral isotretinoin could affect the synaptic activity and
propagation of action potentials along the auditory and ocular
nerve fibers, electrophysiologically.
Materials and methods
Subjects
32 patients (15 men and 17 woman, aged between 21 ± 5.7 years) with
severe nodulocystic acne (n = 30), rosacea (n = 1) and lichen
planus (n = 1) treated with oral isotretinoin (about 1 mg
kg–1 daily) were included in the study. Those with a
history or evidence of otological and ocular disease, familial
hearing loss, oral ototoxic-neurotoxic-oculotoxic drugs or
corticosteroid intake, alcohol abuse, malabsorption, chronic noise
exposure, head trauma, metabolic, neurological, vascular or
autoimmune disease, or any systemic disease such as diabetes,
hypertension and subjects older than 50 years of age were excluded.
Treatment and follow-up
Patients were commenced on an initial high dose (about 0.75-1 mg
kg–1 daily, adjusted according to patients’ tolerance;
Roaccutane®, Roche) which was maintained until the end
of therapy unless intolerance necessitated further dose adjustment.
Isotretinoin was given after meals. Laboratory tests, including
blood count, liver enzymes, serum lipids, and pregnancy tests for
women were done before treatment and at monthly intervals.
Study design
All participitants gave informed consent and underwent
audiological, neurological, ophthalmological and neurophysiological
evaluation before and after treatment with isotretinoin. Clinical
and tympanometric examinations were made by an otolaryngologist for
exclusion of middle ear pathologies. BAER (brainstem auditory
evoked responses) and VEP (visual evoked potentials) were used as
diagnostic tools for the detection of isotretinoin-induced
subclinical side-effects involving the CNS. Otoscopic, audiometric
and BAERs evaluations for both ears and neuro-ophthalmological
examination and VEP examination for both eyes were performed. The
hospital-based ethics committee approved the study.
Audiometric examination
Audiometry was carried out by pure tone audiometer (Interacoustics,
clinical audiometer AC30, Copenhagen, Denmark) in a silent cabin.
Pure-tone thresholds were determined for each ear at the
frequencies of 250 Hz to 8,000 Hz for air conduction and
250 to 4,000 Hz for bone conduction in all patients and
controls. The scale of hearing impairment was assessed according to
the International Standard Organization hearing threshold
parameters (i.e. normal: inability to hear at less than 10 to 20
dB, mild deafness: inability to hear at 27-40 dB, moderate
deafness: inability to hear at 41-55 dB).
Measurement of BAERs
BAERs were measured with Medelec Sapphire Software using two
recording channels with filter bandpass between 100 and
3,000 Hz and these were based on the American EEG society
guidelines [14]. Recording electrodes were attached at the vertex
(Cz, active electrode), both mastoids (reference electrodes) and at
a frontal location midway between the nasion and the vertex (ground
electrode). During testing, all subjects were reclined in a dark
and quiet room. Monaural rarefaction clicks (80-85 dB,
0.1 msec duration) were used as auditory stimuli. White noise
with 30 dB to the contralateral ear was utilized. They were
produced by activating TDH-39 earphones with 0.1 msec pulses at a
8-10/sec rate at an intensity of 70 dB above sensation level for
click. Analysis time was 10 msec with a system bandpass of
100-2,000 Hz. I, III, V wave latencies, amplitudes and I-III,
III-V and I-V interpeak latencies (IPL) were measured and pre- and
post-treatment values in each ear were compared.
The first five peaks of the BAEPs are most probably generated by
the cochlear nerve, the cochlear nucleus, the superior olive, the
lateral lemniscus and the inferior colliculus, respectively
[14-16]. Thus, through the analysis of BAEPs, it is possible to
determine abnormalities in the conduction of the action potentials
along the nerve axons or in the synaptic activity at the neural
brainstem generators. In order to more accurately localize these
abnormalities within the auditory brainstem pathways, a
multiparametric analysis of peak latencies, amplitudes and the
interpeak latencies I-III, III-V and I-V was performed.
Neuro-ophthalmological evaluation
A detailed neuro-ophthalmological examination was performed to
evaluate visual acuity, visual field, colored vision, the fundus
and pupillary function. Patients were evaluated at the beginning
and end of the isotretinoin treatment.
Visual evoked potentials (VEPs)
VEPs were measured with Medelec Sapphire Software, and these were
based on the American EEG society guidelines [14]. VEPs were
recorded to reversal of a checkboard pattern projected onto a
centrally fixated screen whose radius subtended 23° to
the patient’s eye. The patients were placed in the centre of the
screen located at a distance of 90 centimeters. From three to five
stimuli were presented per second. The recording electrodes were
placed O2-OZ-O1 region of the
scalp, the reference electrode was placed in the Fz region using
needle electrodes according to the international system. Analysis
time was 250 msec with a system bandpass of 1-100 Hz. The
P100 peak latency was measured and mean P100 peak latency values
were compared before and after therapy. The values above
110 ms were defined as an abnormal response. This threshold
value was obtained from calculation of the mean value plus 2-2.5
SDs, based upon the normal, age-matched population from the
authors’ database.
Statistical analysis
The Student’s t test for paired samples was performed utilizing the
statistical package for social sciences 11 program (SPSS Inc,
Chicago, USA). The threshold of significance (α) was accepted as
0.05.
Results
Treatment was started at a mean daily dose of 0.75 ±
0.28 mg/kg. The mean duration of treatment with isotretinoin
was 6.2 ± 1.9 months, and the mean cumulative dose was
112 mg/kg ± 29.3.
The most frequent complications were mucocutaneous side effects.
These adverse effects were mild to moderate and improved with
conservative treatment (emollients and artificial tears).
Otological examination revealed no abnormalities either before
or after isotretinoin therapy. No clinically evident adverse CNS
reactions occurred in the treated patients. Before treatment, the
BAEP and VEP data of all patients were found to be within normal
limits. A statistically significant increase of the third
(LIII) and fifth peak latency (LV) in left
and right ear (p = 0.03, p = 0.02 for LIII, p = 0.03, p
= 0.04 for LV respectively), and significant increase of
the first peak latency and IPL I-V in the left ear were found after
isotretinoin administration, as compared to pretreatment (p =
0.0036 and p = 0.02, respectively). No significant differences of
other latencies, IPLs and amplitudes were observed before and after
treatment (table 1). Patients were
informed about the possible significance of these subclinical
findings. All patients who demonstrated subclinical
electrophysiological abnormalities will be followed-up for one
year.
Neuro-ophthalmological examinations were totally normal before
isotretinoin therapy. Patients revealed various abnormalities, such
as primarily diminished visual acuity (n = 5), various visual field
defects (n = 3), abnormal color vision deficiencies (n = 1), dry
eyes (n = 10), blepharoconjunctivitis (n = 10) after treatment. Our
VEP findings are given in table 2. No
significant differences were observed between before and after
treatment, in respect of the value of implicit time of wave P-100
with pattern reversal stimulation. However, a tendency to delay was
clearly observed in the latency of the P100 wave after the
isotretinoin treatment as compared to the pretreatment period. At
least a mathematical increase in latency P-100 wave was also found
in 6 patients after therapy (P100 wave latency: range;
114-143 ms).
Table 1 Comparative evaluation of the BAERs parameters
for for each ear stimulation before and after oral isotretinoin
treatment (n = 32)
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Left ear
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Before therapy
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1.65 ± 0.18
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3.55 ± 0.84
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5.50 ± 0.23
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2.11 ± 0.19
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1.80 ± 0.20
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3.81 ± 0.26
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0.16 ± 0.15
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0.19 ± 0.16
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After therapy
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1.78 ± 0.18
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3.87 ± 0.15
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5.65 ± 0.20
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2.12 ± 0.15
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1.71 ± 0.27
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4.00 ± 0.38
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0.18 ± 0.14
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0.16 ± 0.12
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t
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3.02
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2.10
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2.25
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0.15
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1,49
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2.34
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0.52
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1.001
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p
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0.003
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0.03
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0.03
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NS
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NS
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0.02
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NS
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NS
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Right ear
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Before therapy
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1.74 ± 0.15
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3.78 ± 0.15
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5.52 ± 0.26
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2.10 ± 0.19
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1.71 ± 0.23
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3.82 ± 0.33
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0.15 ± 0.12
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0.14 ± 0.12
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After therapy
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1.80 ± 0.14
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3.88 ± 0.19
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5.62 ± 0.25
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2.09 ± 0.18
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1.74 ± 0.25
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3.89 ± 0.26
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0.21 ± 0.61
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0.22 ± 0.23
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t
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0.95
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2.36
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2.31
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0.32
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9.47
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0.22
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1.44
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1.66
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p
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NS
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0.02
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0.04
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NS
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NS
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NS
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NS
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NS
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Table 2 Comparison of VEP P-100 wave peak before and
after oral isotretinoin treatment for each eye stimulation
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Patern reversal VEP P-100 wave (msec)
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Left eye
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Right eye
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Before therapy
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Mean ± SD
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107.15 ± 11.46
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108.35 ± 12.33
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After therapy
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Mean ± SD
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110.27 ± 11.23
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110.38 ± 12.59
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t
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0.39
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0.13
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p
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NS
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NS
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Discussion
Over the last decade, accumulating evidence has indicated that
natural and synthetic retinoids may be capable of affecting the
growth, differentiation and function of nervous tissue in vivo and
in vitro [4-7]. A spectrum of central nervous system adverse
reactions similar to those observed in the hypervitaminosis A
syndrome have been reported in a relatively small number of
patients under oral synthetic retinoids, especially isotretinoin,
etretinate or acitretin [1-3].
In view of the findings of the present study, it seems
reasonable to suggest that these subclinical changes may be due to
an isotretinoin-induced synaptic dysfunction or to a conduction
defect in the auditory and ocular nerve fibers. Similar to our
results, in several reports the electrophysiological and/or
clinical findings suggested a causal association between an
acquired CNS neurotoxicity or neuropathy (maybe with
demyelinization features) and oral retinoids [8-11, 17-20].
Neurophysiological abnormalities indicative of CNS dysfunction
have been reported in patients treated with oral etretinate, the
parent compound of acitretin [8-10]. In a recent study,
abnormalities of the auditory evoked potentials were detected in 9%
of the patients tested after 3 weeks of oral etretinate therapy,
which completely reversed within 6-9 months after cessation of
treatment [8]. Interestingly, decreased hearing was reported also
in a patient with oral papillomatosis who was orally treated with
high etretinate doses [9]. In another study, alterations of
somatosensory evoked potentials were observed in 7 of 8 patients
after long-term oral etretinate administration [10]. On the other
hand, to the best of our knowledge, the evaluation of the
neurophysiological abnormalities of CNS functions of isotretinoin
has been reported in only one study by Nikiforidis et al. [11].
Interestingly, subclinical changes of the auditory brainstem
response have been observed in 9% of patients treated orally with
isotretinoin over a period of 3 weeks. A tendency to delay has also
been clearly observed in the latency of the fifth peak and in the
IPL I-V after isotretinoin treatment [11]. In the present study, no
clinically evident CNS adverse reactions occurred in the treated
patients, and both the otological examination and conventional
audiometry failed to reveal any abnormalities due to oral
isotretinoin therapy. A statistically significant increase of the
third and fifth peak latency in both ears, and significant increase
of the first peak latency and IPL I-V in the left ear were found
after isotretinoin administration, as compared to the pretreatment.
No significant differences of other latencies, IPLs and amplitudes
were observed before and after treatment. The first peak latency is
primarily related to auditory nerve functions. The increased third
and fifth peak latency and I-V IPL are related to the pathology of
the superior olivary nucleus and inferior colliculus or abnormal
synaptic activity, transmission of the action potential from the
auditory nerve to the cochlear nucleus and the latter to the
superior olivary nucleus and inferior colliculus [15, 16].
Alternatively, it may be associated with a delayed synchronization
of action potentials in these nuclei. Moreover, a case of
stiff-person syndrome recently reported in a patient under
treatment with oral isotretinoin indicates that this compound may
also be capable of affecting the motor control mechanisms of the
CNS [20].
Sadick et al. [17] reported a child with lamellar ichthyosis who
had been treated with 13-cRA for hyperkeratotic dermatoses; the
child died following an abrupt episode of severe hypotension. The
authors performed a detailed postmortem pathological investigation,
which revealed spongiform myelinopathy of the white matter tracts
in the brainstem tegmentum and cerebellar hemispheres. Although the
specific cause of the CNS myelinopathy was unknown in this
particular case, the authors suggested that high-dosage systemic
13-cRA treatment could have had a role. Yaman et al. [18] reported
the case of a demyelinating lesion located in the left cerebellar
region that developed 3 months after the onset of oral isotretinoin
treatment. Cranial magnetic resonance imaging (MRI) scan showed a
cerebellar lesion. One month after the cessation of oral
isotretinoin treatment, the lesion became less prominent on the MRI
scan, and after 3 months, it had disappeared. The authors suggested
alerting physicians to the possibility of a causal link between the
demyelinating cerebellar lesion and isotretinoin treatment.
Guillain-Barré Syndrome (GBS) is another neurological side-effect
reported as secondary to isotretinoin treatment for acne. Recently,
Pritchard et al. [19] also reported a diagnosis of GBS for two
patients taking oral isotretinoin to treat severe acne.
In neuro-ophthalmological examination, various abnormalities
such as diminished visual acuity, abnormal color vision, dry eyes,
various visual field defects and blepharoconjunctivitis were found
after treatment. To the best of our knowledge, this paper
represents the first study evaluating the VEP findings under oral
isotretinoin therapy. No statistically significant differences with
regard to the value of implicit time of wave P-100 with pattern
reversal stimulation were found between the beginning and end of
the isotretinoin treatment. Even so, the possibility that
isotretinoin may affect the synaptic activity and propagation of
action potentials along the ocular nerve fibers and have an adverse
effect on retinal functions can not be definitely ruled out. An
increased latency of P100 wave was detected after therapy in 18% of
patients treated orally with isotretinoin in this study.
Fraunfelder et al. [21] described ocular inflammation, optic
neuritis and pseudotumor cerebri in patients who had been treated
with isotretinoin but could not find a definite cause and effect
relationship between the drug and ocular pathology. Weleber et al.
[22] found abnormal retinal function associated with isotretinoin.
They suspected a competition of isotretinoin for retinol binding
sites on cell surfaces or transport molecules. An alternative
explanation not ruled out here or in the present study, is the
possibility that the binding sites that should have been occupied
by retinol were not occupied because of dietary deficiency,
mis-choice, or malabsorption [23, 24]. Feighl et al. [25] reported
abnormal retinal function due to interferon/isotretinoin therapy in
a case with cutaneous malignant melanoma. But they postulate that
visual complaints are caused with a high probability by
melanoma-associated retinopathy although, in the literature,
isotretinoin is described to show similar effects on retinal
function [25]. Nevertheless, to exclude a toxic retinopathy due to
isotretinoin, they still recommend a complete ocular examination
including electrophysiological evaluation, dark adaptometry, color
vision and visual field testing when starting therapy with a
synthetic retinoid.
The mechanisms by which retinoids can affect the development and
function of the nervous system at the molecular and cellular level
are currently under investigation [4-7]. All-trans retinoic acid is
known to regulate development, proliferation, differentiation and
function of a variety of cell lines, including neural precursors
[6, 7] and the anteroposterior patterning of the central nervous
system, particularly of the hindbrain [25, 26]. In view of the
pleiotropic effects of retinoids on nervous tissue in concert with
protein growth factors [26, 27], a metabolic rather than a toxic
mechanism seems to better explain nerve conduction abnormalities
(synaptic malfunction or a conduction defects) in our patients.
Indeed, this metabolic problem may stem from deficiency of retinol
at the receptor [23, 24]. Alternatively, abnormal central nervous
conduction may be associated with changes in the lipid composition
of the nervous membranes related to oral isotretinoin therapy
[10].
The potential risk for neurological side-effects and toxicity of
isotretinoin, a drug that has been increasingly used in recent
years, should be followed up by experienced clinicians, since this
retinoid is currently prescribed to large numbers of mostly young
patients worldwide. These changes seem to be of interest for
neurophysiologists rather than clinicians. However, the findings of
present study and other reports indicate that oral isotretinoin
might be capable of causing CNS conduction abnormalities. Although
it is difficult to determine the causal association between the
neuroelectrophysiological findings and isotretinoin treatment, we
would like to alert physicians to this possibility. Clinicians
should be aware of possible neurological sensorial symptoms during
isotretinoin therapy. The exact clinical significance of the
isotretinoin-induced neurophysiological alterations reported here
remains to be determined in further studies. We conclude that oral
isotretinoin therapy leads to alterations in the central nervous
system, as determined by BAEP and VEP recordings, and it seems
reasonable to suggest that neurophysiological and neurological
evaluation of audiological and ocular nerve (or retinal) function
should be added to the list of investigations that are performed in
patients reporting symptoms (e.g. hearing loss, decreased visual
acuity) before, during and after treatment with oral isotretinoin.
Our results also suggest that evoked potentials could be useful
non-invasive tests for detecting and monitoring subtle subclinical
side-effects of isotretinoin therapy on CNS.
Acknowledgements
Financial support: none. The authors have no conflict of interest
to declare.
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