Mozart's music in children with drug-refractory epileptic encephalopathies
Highlights
- •
- Mozart's music has been tried in children with refractory encephalopathies.
- •
- Music therapy decreased seizure recurrence in about 45% of children.
- •
- All responders also had an improvement in nighttime sleep and daytime behavior.
Abstract
Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal EEG discharges and recurrence of clinical seizures in both adults and young patients. In this prospective, open-label study,
we evaluated the effect of listening to a set of Mozart's compositions,
according to the Tomatis method, on sleep quality and behavioral
disorders, including auto-/hetero-aggression, irritability, and
hyperactivity, in a group of children and adolescents with drug-resistant epilepsy.
The
study group was composed of 11 outpatients (7 males and 4 females),
between 1.5 years and 21 years of age (mean age: 11.9 years), all
suffering from drug-resistant epileptic encephalopathy (n = 11). All of them had a severe/profound intellectual disability associated with cerebral palsy.
During the study period, each patient had to listen to a set of
Mozart's compositions 2 h per day for fifteen days for a total of 30 h,
which could be distributed over the day depending on the habits and
compliance of each patient.
The music was filtered by a
device preferably delivering higher sound frequencies (> 3000 Hz)
according to the Tomatis principles. The antiepileptic drug therapy
remained unchanged throughout the study period. During the 15-day music
therapy, 2 out of 11 patients had a reduction of 50–75% in seizure
recurrence, and 3 out of 12 patients had a reduction of 75–89%.
Overall, 5 (45.4%) out of 11 patients had a ≥ 50% reduction in the total
number of seizures, while the percentage decrease of the total seizure
number (11/11) compared with baseline was − 51.5% during the 15-day
music therapy and − 20.7% in the two weeks after the end of treatment.
All responders also had an improvement in nighttime sleep and daytime
behavior.
Keywords
1. Introduction
Among the so-called alternative nonpharmacological treatments for drug-resistant epilepsy, in addition to surgery, vagus nerve stimulation, ketogenic diet, and deep brain stimulation, there is a growing interest in music therapy.
In
fact, there are a few studies reporting that the musical stimulation,
particularly the “Mozart effect” of the K448 sonata for two pianos, is
able to decrease both interictal EEG discharges [1], [2] and [3] and recurrence of clinical seizures [4], [5], [6], [7] and [8].
As to the interictal discharges, there is some evidence for the particular responsiveness of generalized and central spike-and-wave discharges to music therapy [3], with an effect that persists even after discontinuing music stimulation (“carryover effect” according to Lin et al. [2]).
With respect to clinical seizures, there is only a randomized controlled trial [8] in adults with epilepsy and neurological disorders,
and there are a few other small studies in children and adolescents
with several forms of epilepsy (particularly idiopathic), with protocols
differing for duration and kind of musical stimulation (especially
Mozart K448 for 2 pianos) and length of follow-up [3], [4], [8] and [9].
In this prospective, open-label trial, we evaluated the effect of listening to a set of Mozart's compositions, according to the Tomatis method [10], on seizure
recurrence, sleep quality, and behavioral disorders, including
auto-/hetero-aggression, irritability, and hyperactivity, in a group of
children and adolescents with drug-resistant epileptic encephalopathies.
2. Materials and methods
The patients were recruited from the center for children and adolescent epilepsy care of the Medical School of the University of Salerno.
They were selected according to the following criteria: (i) 12 months of age and over; (ii) with seizures refractory to antiepileptic drugs; (iii) with drug-resistant
epilepsy and with at least four seizures a week during the 6 months
before music therapy was administered; (iv) without systemic or
progressive neurologic diseases (including deafness); and (v) with
informed consent by parents and/or caregivers to participate in the
study. Exclusion criterion was poor compliance with following the study
protocol.
The protocol was approved by the Ethics Committee, and the study was not sponsored by any commercial organization.
Nonepileptic seizures were excluded by means of video-EEGs and/or long-term monitoring EEGs. Brain computed tomography/magnetic resonance imaging scans were performed in all cases. Seizure
frequency, type, and duration were recorded by parents and caregivers,
both at home and at school, in an epilepsy diary. Seizures were
classified according to the International League Against Epilepsy (ILAE)
classification of epileptic seizures [11].
The effectiveness of music therapy was rated as follows: seizure-free
(100% remission); very good (50–98% decrease in seizure frequency);
minimal (seizure frequency less than 50% with minimal change in seizure
severity); and unmodified or worsened (seizure frequency and severity
similar to [unmodified] or worse than [worsened] baseline).
Before
starting the treatment (TIME 0), each patient was administered a
questionnaire, designed to evaluate seizure frequency and type, quality
of nocturnal sleep, and daytime behavior (irritability, fits of rage,
crying spells, self-/hetero-aggression) throughout the 6 months prior to
treatment onset. Laboratory evaluation including antiepileptic drug
blood level, a full blood count, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), urea,
creatinine, and urinalysis, together with a sleep–wake video-EEG
recording, was performed in each patient in the previous week.
On
the same day, a wake video-EEG recording before, during, and after
listening to the music of the same duration (20 min, respectively) was
performed in each patient.
Soon
after, each child was delivered with a device, and his/her
parents/caregivers had an exhaustive training for home treatment.
Parents
were also given an epilepsy diary in which they had to record seizure
number, type, and duration both at home and at school as well as changes
in the quality of nocturnal sleep and daytime behavior.
The
set of music to be administered included Mozart's compositions
(symphony no. 41, k551; piano concerto no. 22, k482; violin concerto no.
1, k207; violin concerto no. 4 in D major, K218, allegro aperto;
symphony no. 46 in C major, kv96, allegro; flute concerto in D major
K314, allegro aperto).
Mozart's compositions were modified by a device, the so-called “electronic ear”, [10].
The latter, through a system of filters, amplifiers, and sophisticated
mechanisms of electronic gate, modifies the amplitude of sound
frequencies preferably delivering higher sound frequencies
(> 3000 Hz) which, according to Tomatis, “recharge” the cerebral
cortex. The electronic ear works on the middle ear through the
contraction of the muscles of the hammer and the bracket.
The
sound is transmitted through both air conduction and bone conduction.
Through the air, the sound signal reaches the eardrum, whose active
vibration stimulates the cochlea
in the inner ear. Through bone conduction, the sound message is
transmitted directly on the skull from a vibrator placed on the top of
the cap. The sound, in this way, directly reaches the inner ear,
bypassing the eardrum.
The
music had to be listened to 2 h per day for fifteen days for a total of
30 h and listening time could be distributed over the day depending on
the habits and compliance of each patient. At study entry, parents were
given a password to access a dedicated website and listen to Mozart's
compositions. In this way, full compliance with the study protocol could
be monitored. If daily music listening was irregular or insufficient, a
given patient would be excluded from the study.
After
15 days (TIME 1), each patient underwent a second wake video-EEG
recording lasting 20 min. The music device and the filled-in diary
regarding the first 15 days of treatment were retrieved, and a blood
sample for antiepileptic drug level evaluation was taken. Parents were
then given a new diary to record seizure recurrence and type together
with nocturnal sleep quality and behavioral changes during the next
month in the absence of music stimulation.
After
1 month (TIME 2), a wake video-EEG recording was then performed on each
patient. Throughout the study, no changes to the antiepileptic
treatment or addition of other drugs, except rescue drugs, were allowed.
Statistical analysis was performed by means of SPSS (SPSS Inc., USA, 2006). Data are expressed as mean ± SD. The paired t-test
was used to compare the percentage reduction in seizure frequency
throughout the music therapy with the premusic seizure frequency set at
100%. Analysis of variance two-way analysis of variance was carried out
to compare percentage seizure frequency reduction after listening to
Mozart's set of compositions with respect to sex, etiology, IQ, and
seizure type. A p-value less than 0.05 was set as significant.
3. Results
The
study group was composed of 11 outpatients (7 males and 4 females),
between 1.5 years and 21 years of age (mean age: 11.9 years), all
suffering from drug-resistant epileptic encephalopathy (n = 11).
All
patients (11/11) had a severe/profound intellectual disability
associated with cerebral palsy (spastic tetraparesis with or without
dystonia, n = 9; double hemiparesis, n = 1; right hemiparesis, n = 1).
The clinical EEG and neuroradiological features of each patient are summarized in Table 1.
- Table 1. Clinical characteristics of patients.
Patient Sex Age
(years)Epilepsy type PMD/IQ Neurological examination Brain MRI EEG Seizure type AED therapy 1 M 16 Epileptic encephalopathy Severe Double hemiparesis Atrophy; polymicrogyria Multiple foci Fixed gaze and upper limb hypertonus TPM–CBZ–RUF–CZP-(KD) 2 M 12 Epileptic encephalopathy Profound Spastic tetraparesis Periventricular leukomalacia Multiple foci Right side hypertonus with head deviation PB–CBZ-(KD) 3 M 16 Epileptic encephalopathy Profound Spastic tetraparesis Brain migration disorder Generalized SW Tonic seizures (10 s) VPA–PB–LEV–clobazam 4 F 9 Epileptic encephalopathy; LYS1 deletion Profound spastic/hypotonic cerebral palsy Lissencephaly Multiple foci and generalized SW Cluster of eating-induced spasms VPA 5 M 5 Epileptic encephalopathy; CMV infection; microcephaly Profound Spastic tetraparesis Brain atrophy; multiple calcifications Diffuse and focal S and polyspike W Cluster of asymmetric spasms RUF–PB–VPA–GVG 6 M 8 Epileptic encephalopathy Profound Spastic/distonic tetraparesis Brain atrophy; polymicrogyria Multiple foci Tonic spasms CBZ–PB–GVG–LEV–BDZ–baclofen 7 M 21 Epileptic encephalopathy Severe Spastic tetraparesis Brain atrophy Multiple foci Generalized clonic seizures PB–OXC–CZP–LCM 8 F 11 Epileptic encephalopathy Severe Spastic tetraparesis Brain atrophy Right frontal–occipital SW Head and eye version with limb tremor CBZ–clobazam–PB 9 F 1.5 Epileptic encephalopathy Severe Right hemiparesis Hemimegalencephaly SW discharges over right hemisphere Cluster of spasms VPA–GVG–PB 10 F 15 Epileptic encephalopathy, chrom. 14, monosomy, chrom. 9 trisomy Profound Spastic tetraparesis Bilateral polymicrogyria Multiple foci Generalized hypertonus PB–TPM–clobazam 11 M 17 Epileptic encephalopathy Severe Spastic tetraparesis Brain atrophy Polyspike and wave discharges Fixed gaze and unresponsiveness VPA–TPM–LTG–NZP - CBZ, carbamazepine; PB, phenobarbital; LEV, levetiracetam; VPA, valproic acid; LTG, lamotrigine; OXC, oxcarbazepine; VIG, vigabatrin; TMP, topiramate; RUF, rufinamide; KD, ketogenic diet; BDZ, benzodiazepine; NZP, nitrazepam; PMD, psychomotor development; IQ, intelligence quotient; AED, antiepileptic drug; MRI, magnetic resonance imaging; EEG, electroencephalogram; SW, spike and wave.
The mean number of the antiepileptic drugs was 3.4; two patients were also on a ketogenic diet.
Seizure recurrence relative to all patients before, during, and after music therapy is shown in Fig. 1.
During the 15-day music therapy, 2 out of 11 patients had a reduction
of 50–75% in seizure recurrence, and 3 out of 12 patients had a
reduction of 75–89%. None of the patients were seizure-free. The
remaining patients showed minimal or no changes in seizure frequency (a
decrease of 25–49% in 2, less than 25% in 2, and unchanged in the other
2). Overall, 5 (45.4%) out of 11 patients had a ≥ 50% reduction in the
total number of seizures, while the percentage decrease of the total
seizure number (11/11) compared with baseline was − 51.5% during the
15-day music therapy and − 20.7% in the two weeks after the end of
treatment. The average percentage seizure reduction for all patients at
the end of music treatment compared with the premusic seizure frequency
was 48.4 ± 48.7% (CI = 56 ± T(10) ∗ 21.18662, p = 0.02; Student's t-test).
No statistically significant difference was observed between patients
with different severities in IQ (p = .111), etiology (p = .109), gender
(p = .107), and seizure type (p = .107).
- Fig. 1.Total number of daily seizures among the enrolled patients (N = 11) prior to music exposure and during and after music therapy. *, p = 0.02 (Student's t-test).
With
respect to the relationship between the response to music therapy and
the localization of spike-and-wave discharges, occipital/bioccipital
discharges were present in 20% of the responders and in 66.7% of the
nonresponders (Fig. 2).
- Fig. 2.Comparison of occipital foci between responders and nonresponders.
Nighttime
sleep was improved (easier falling asleep and less early morning
awakenings) in 4 (36.4%) out of 11 patients; all were included among
responders. One of the responders, however, had a regular sleep before
treatment.
According to their
relatives, all responders also presented a behavioral improvement,
i.e., being more quiet and attentive to the environmental stimuli.
Treatment compliance was generally good both in children and in parents.
4. Discussion
In
this short-term prospective study, music therapy, consisting of a set
of Mozart's compositions administered according to the principles of the
Tomatis method, was associated with a significant reduction in seizure
recurrence and an improved daytime behavior and quality of nighttime
sleep in about 45% of children and adolescents with drug-resistant
epileptic encephalopathies associated with psychomotor developmental
delay/intellectual disability.
Currently, there are a few reports on the effect of music listening on interictal epileptic discharges [1], [2] and [3] and seizure recurrence [4], [5], [6], [7] and [8].
Lin et al. [2]
report a reduction of interictal discharges from different foci
following administration of Mozart's K448 sonata for 2 pianos in D major
in children with epilepsy. The reduction was more evident for
generalized and parietal spike-and-wave discharges, employing a piece of
music with more fundamental tones and lower harmonic frequencies. These
authors concluded, therefore, that it is possible to reduce the
interictal epileptogenic discharges in some patients by optimizing the
fundamental tones and by minimizing higher harmonic frequencies.
The
long-term efficacy (> 6 months) of Mozart's K448 on interictal
epileptogenic discharges was later confirmed by Lin et al. [3] in 18 children suffering mainly from idiopathic epilepsies. These authors also reported a best response in nonoccipital foci.
With respect to the effect of music listening on seizure recurrence, there is currently only one randomized controlled study [8] and a few open trials.
Lin et al. [7]
evaluated the efficacy of music therapy in 11 children, between
2.9 years and 14.4 years of age, with refractory cryptosymptomatic
epilepsy, and treated for 6 months with music stimulation consisting of
Mozart k448 every night for the duration of 8 min.
During
the 6-month treatment, a > 50% seizure reduction was achieved in
72.7% of the patients, including 2 who were seizure-free. No correlation
was observed with IQ, etiology, and sex. The best response was reported
in generalized seizures. In the only randomized controlled trial,
conducted by Bodner et al. [8],
music therapy (Mozart K448) was administered to an institutionalized
adult population with refractory epilepsy and mental retardation
followed-up for 3 years. The music stimulation was administered for the
full night sleep, at regular intervals of 8.5 min each per hour for one
year, leading to a 24% reduction of the total seizure recurrence
compared with baseline period and a “carryover” effect after
discontinuation of − 33% of the total seizure number.
Interestingly, a significant effect on seizure recurrence was reported in a few adults with focal-onset drop attacks [4] and [5] and in two patients with nonconvulsive status epilepticus [6] and [9].
More recently, Lin et al. [12]
investigated the effect of listening to Mozart K.448 in reducing the
seizure recurrence rate in children with first unprovoked seizures, most
of them with idiopathic, benign forms of focal or generalized epilepsy
and normal intellectual functioning. After a six-month follow-up,
listening to Mozart K.448 significantly decreased the seizure recurrence
rate and the amount of spike-and-wave discharges.
In
our series, the particularly severe epileptic encephalopathies in all
patients in a context of delayed psychomotor development/intellectual
disability and cerebral palsy could, to some extent, explain why music
therapy was less effective and associated with a smaller carryover
effect compared with Lin et al. [2].
In
our sample, although interictal spike-and-wave discharges were overall
unchanged (possibly due to the clinical severity in all patients), there
was, nonetheless, a significantly lower incidence of occipital foci in
responders (20% vs. 66.7% in nonresponders) in agreement with Lin et al.
[3].
Indeed, central, frontal, temporal, and parietal discharges as well as
bursts of generalized spikes and polyspike-and-wave discharges were
present mainly in the responder group.
In this regard, Lin et al. [3]
suggest that occipital foci could be excluded from the
temporal–parietal–frontal auditory network. These data, of course, need
to be further studied.
Of
interest is the apparent beneficial effect of music therapy on nocturnal
sleep as reported in some of our children. Parents, in fact, reported a
decrease in time to fall asleep, with fewer nighttime awakenings and
less early morning awakenings. Similarly, some children showed a
behavioral improvement consisting of reduced self-/hetero-aggression,
less irritability, and mood instability with less frequent crying
spells. Whether there is a correlation between improved sleep and
reduction in seizures will require further study.
Improved
attention and participation to the environmental stimuli in some
children, not reported so far, to our knowledge, might be correlated
with the beneficial effect of music therapy on mood [13] as well as on cognition [14] and with the well-known effect of activation of parasympathetic tone [15].
As
to the kind of music, in the present study, a set of Mozart's
compositions with musical instruments other than pianos and rhythmic
characteristics somewhat close to K448 were used in order to assess a
potential alternative to K448. Music strings with high harmonics
(> 3000 Hz) were also selected according to the principles of the
Tomatis method based on the electronic ear [10].
According
to Tomatis, indeed, high-frequency sounds are an important form of
stimulation for the brain. It is, in fact, well known that 80% of the
34,000 hair cells in the cochlea respond to sound above 3000 Hz.
Accordingly, a modified device based on the Tomatis principles provided
high-frequency filtered music by means of electronic gating.
The
transosseous sound transmission offered by the headset allows us to
directly convey the sound to the inner ear. As for the optimum length of
the music stimulation, it is so far not well established. In the
present study, we decided to extend it to 2 h each day (whether in
wakefulness or sleep), also in view of the clinical severity in our
patients, who appeared generally compliant with this treatment.
Furthermore,
the use of headphones was considered, firstly, to avoid noisy
environmental interference with the music listening and, secondly, to
avoid potential poor compliance in the family group. A wider set of
musical compositions was also selected to improve children's compliance
with music listening.
4.1. Limitations and strengths of the study
The
limitations of this study are mainly the study design (nonrandomized,
prospective, open-label), the small sample size, and the short-term
duration. The homogeneity of the sample (all children with severe,
refractory epileptic encephalopathies and intellectual
disability/cerebral palsy), the use of music other than Mozart's sonata
for two pianos in D major, K448, the use of music strings with high
harmonics (> 3000 Hz) according to the principles of the Tomatis
method, based on the electronic ear, close monitoring of each patient
throughout the study with respect to behavioral changes and sleep
quality, together with a longer duration of daily music listening, and
an unchanged drug therapy during each single study phase may represent
potential strengths.
In
conclusion, this study appears to confirm what has been reported so far
on the effectiveness of music therapy on seizure recurrence and
behavioral improvement in some children with refractory epilepsy,
although there is still a need for further controlled studies both on
clinical effectiveness regarding, in particular, seizure type,
localization of epileptiform discharges, and patients's age, and on the
kind and duration of music stimulation.
We, of course, agree with Maguire [16]
that there is limited evidence for an anticonvulsant effect of music
listening in epilepsy so far and that its therapeutic potential remains
for the moment largely unproven, with our understanding of the involved
brain mechanisms being very limited.
However,
the clinical improvement in some children and the significant parents'
satisfaction at the end of this preliminary study encourage us to
continue the objective assessment of this promising, complementary
treatment of epilepsy.
Conflict of interest
All authors declare the absence of any potential conflicts of interest.
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