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TUBEROUS SCLEROSIS IN A CHILD WITH EPILEPSY,
AUTISM AND MENTAL RETARDATION.
REPORT OF THE REHABILITATIVE AND DRUG THERAPY INTERVENTION.
CRIVELLI C., DONATI A. and R. COCCHI
Cooperativa CIFFRE, via D’Azeglio 2 – 37123
Verona
Abstract
The
paper reports the case history of a male child with Tuberous Sclerosis and
autism from birth to 9 yrs and 7 months.of age. The Authors are following this boy with a psychomotor
rehabilitative intervention and with a pharmacological therapy. Impressive
results on autistic symptoms and cognitive development are described.
Key words: Tuberous sclerosis, autism,
mental retardation, rehabilitation, drug therapy.
Other genetic and chromosomal anomalies
Drug modulation of stress reactions
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Tuberous Sclerosis (or the
Bourneville's disease) (TS) is a disease of cellular differentiation and
proliferation. People inherit it as an autosomal dominant trait with variable
penetrance and a high spontaneous mutation rate. Lesions occur in the brain,
skin, kidneys, heart, and other organs.
Recent studies suggest
genetic heterogeneity, with at least two gene loci on chromosome 9, 16 and
perhaps 11 (Roach and Delgado, 1995). The feature of this disease is the
clinical triad of convulsive seizures, mental deficiency And sebaceum adenomas.
Usually, the onset is
usually the appearance of convulsive seizures or the delay in psychomotor
development. Actually the earliest skin lesions are ash-leaf-shaped pale
pigmented spots ("white
spots") over the trunk and limbs. They are distinguishable by size, shape
and character from vitiligo and non vascular nevi.
The sebaceum adenomas or
tubers vary in size from 0.1 to 1.0 cm, push up the skin and are pinkish or
pinkish yellow in colour. They spread predominantly in a butterfly like
distribution over the cheeks, nose and forehead.
CT scan shows calcified
nodules, particularly in the temporal lobes and next to the ventricles. The EEG
is usually abnormal but without any specific pattern. Cognitive functioning may
vary from severe mental retardation to average intelligence.
These varying features,
which are common to autism, mental retardation and seizures, induced the
Authors to present this case history. In it every one of these aspects showed a
positive evolution, following a combined approach, both rehabilitative
psychomotor and pharmacological.
Case history
He was a male, born in
1989. The child's father had grand mal seizures, and his skull X rays showed
signs of endocranial calcifications. His father had pale spots diagnosed as
pityriasis.
During pregnancy his mother
had reduced blood iron, treated with iron throughout. At 8 mos. his mother took
antibiotics for flu. She went through regular controls, without major concern.
The delivery occurred at 41 weeks with a 3750-g birth-weight and the Apgar Rate
was 9 at 1 minute, and 10 at 5 minutes. On 4th day an echo-ECG showed a cardiac
rhabdomyoma.
Parents' reports and
pediatrician reports assert a regular development both physical and
neurological in early months. At the end of three mos. a seizure occurred with
mouth stretching to left and little tremors throughout the body. After this,
frequently severe seizures occurred, characterized by staring and revolving
eyes, mouth stretching and tremor, and a semiconscious state.
A drug therapy was set up:
Valproate 50 + 50 + 100 mg.
Nitrazepam 2 + 2 + 3 drops.
Seizures increased until 15/20
times per day (mouth stretching to left, sudden flexion and adduction of upper
limbs, flexion of the head and lower limbs).
Meanwhile, a neuropsychic
regression occurred. One could observe inconsistent visual and auditory
pursuit, and protrusion movements of the tongue. The child didn't anticipate
head control to traction, he could poorly raise the head in prone position.
At five mos.:
The child condition on a CT
scan basis had the diagnosis of Bourneville's Tuberous Sclerosis, with
symptomatic epilepsy. The EEG showed disorganized activity with focal paroxysms
especially from right half-brain and generalized.
At eight mos.:
The child presented 10/12
clusters of seizures. Their onset was always as mouth stretching to the left
side, sometimes revolving eyes, and flexion spasms on upper and lower limbs and
the head. The EEG reported abnormal rhythm organization, polymorphic non
synchronous activity with inconsistent prevalence on left half-brain. It
detected also polymorphic paroxysmal elements with high voltage waves and
spikes in multifocal representation.
Neurological examination showed
eyes in the axis, pupils with good reaction to light, good visual pursuit.
Moderate and symmetric hypotony especially on the trunk. Fair head control, no
trunk control. He can reach supine position from being on one side, but not
vice versa. He localizes mother voice, sometimes smiles, makes different
sounds, can grab each other hands.
Current drug therapy:
Valproate 70 + 70 + 100 mg.
Clobazam 10 mg, 1/2 + 1/2 + 1
tabs.
Phenobarbital 15 mg, 1/2 + 1
tabs.
At 12 mos.:
Seizures had no change, so
an increase of both valproate and clobazam was decided, and, after a while,
clobazam was substituted by clonazepam. Seizures showed a little decrease, but
there were some neuropsychic regressions. The neurologist stopped clonazepam
and reintroduced clobazam (dosage not known) but the seizures persisted without
change and no neuropsychic progress came out.
At 14 mos.:
Seizures cluster 10 times
per day, same type. EEG: Awake tracing without any generalized paroxysm.
Sleeping tracing: In the 2-3 phase an asymmetric organization was detected due
to reduced left stability. In the left half-brain were noticed slow waves and
waves-and-spikes on the anterior temporal lobe.
Current drug therapy:
Valproate 150 + 100 + 150
mg.
Phenobarbital 15 mg, 1 + 1 +
1/2 tabs.
Clobazam 1/2 + 1/2 + 1 tabs.
Neurological examination
showed behavioural instability and hyper-excitability, and difficulty in eyes'
contact. One did observe stereotyped movements and fair head's control. The
child could roll both sides. In standing position some hypertonus of lower
limbs emerged. At this time a rehabilitation intervention started twice a week
in a local rehabilitation centre.
At 2 yrs.:
More severe seizures at
awakening, they are 6-7 per day, with some cluster.
Based on the blood drug dosage the drug therapy changed in:
Valproate 200 + 100 + 200
mg.
Phenobarbital 15 mg, 1 + 1 +
1/2 tabs.
Clobazam 10 mg, 1/2 + 1/2 + 1
tabs.
At 2 yrs. and 3 mos.:
Seizures' situation had
some improvements.
Current drug therapy:
Valproate 180 + 70 + 250
mg.
Phenobarbital 15 mg, 1 + 1/2 +
2 tabs.
Clobazam 10 mg, 1 + 1/2 + 2
tabs.
Health status worsened due
to wintertime, the child was prone to catch illnesses, colds, and ear
infection. The child had sleeping rhythm very disturbed and so he woke up often
per night crying.
Neurological-functional
examination presented the child as now able to reach and maintain sitting
position with fair balance control, and beginning to walk if helped. Sensory
interaction and environment participation seem fragile. More stereotyped
movements are present. Some deafness was suspected, but not confirmed. The
child was attending the rehabilitation therapy twice per week.
At 2 yrs. and 5 mos.:
Current seizures'
situation: from 1 to 3 times per day seizures occur characterized by head
flexion, stiffness throughout, staring eyes and panting breathing; Ten times
per day absences and mouth stretching. The EEG showed paroxysmal elements
especially on temporal areas of right half-brain, with synchronous and
asynchronous pathways on both half-brains. Paroxysmal discharges' onset at 10
cps followed by slow spike-and-wave suggested a seizure tracing.
Drug therapy:
Phenobarbital was ceased
and substituted by carbamazepine:
Valproate 180 + 70 + 250 mg.
Clobazam 10 mg, 1/2 + 1 tabs.
Carbamazepine 100 + 100 + 100
mg.
At this time, the child's
parents contacted two of the authors who are members of CIFRRE asking a more
specific and intense rehabilitative program. Neuro-psychological evaluation
showed very poor environment participation and fair hyperactivity.
Sensory function appears
good (saccadic movements, visual convergence and sounds' localization were all
present), the child is unable to fixate and seems not interested in parents'
voices.
Moreover, the examiners
detected tactile hypersensitivity throughout the body, poor proprioception and
movement awareness. He could maintain sitting position. If you put him to
stand, he can move some steps raising arms over the head with wide feet base,
but this walking is not functional. He had also ataxic attitude, very poor
balance, great fear when moved in the space, and stereotyped movements
involving the trunk, head, hands. The latter are not used to grasp. He can make
sounds, without any communication intent.
The staff suggest a very
intense program of sensory stimulations (tactile, visual and auditory) and
motor opportunities (rolling, somersault, hanging, spinning a chair). They
advised milk and dairy product elimination because history and a positive
allergy test previously done.
At 3 yrs.:
Seizures had slightly
improved in terms of frequency (1-2 stiffness, staring eyes, head flexion, and
5-6 absences per day). The neur.-psychological evaluation showed a better
situation. Now he can fixate and follow people with eyes for few seconds,
understand some words (his name, "let's go out," "food is
ready"). Now he can crawl on hands and knees, reach a kneeling position
and stand up by himself, can go down from a sofa or a bed. He can walk around
independently. Stereotyped movements did not improve, and the child puts his
hands in the mouth, can drink from a cup, makes more sounds.
Our staff suggest
continuing all activities and to add an NTM stimulation everyday (Donati and
Moniga, 1992; Donati and Crivelli, 1997).
Control CT scan reported:
the picture of tuberous sclerosis has no modification, and is characterized by
bilateral calcified subependymal nodules on lateral ventricles. There are some
alterations on cortico-subcortical parenchyma in the left temporal lobe,
presumably in white substance of right corona radiata and of left anterior
convexity.
These alterations suggest a
suffering state of white substance, but also of grey substance in the left
temporal lobe. This evidence shows an evolution of the disease and deserves a
CT scan control in 3-5 mos.
At 4 yrs.:
There were 1-3 seizures as
before and 8-10 absences per day.
Current drug therapy:
Carbamazepine 100 + 100 +
300 mg.
Valproate 100 + 100 + 300 mg.
Clobazam 10 mg, 1/2 + 1 tabs.
Seizures vary a lot from
day to day because they seem influenced by different factors, changing weather,
intercurrent infective illnesses. The child started to attend kindergarten in
this period, and he
caught many respiratory infective and exanthematic illnesses: measles, chicken
pox, colds and frequent ear infections. Sleeping rhythm became very disturbed,
with periods of insomnia.
Neuro-psychological
observation put in evidence better motor and relational ability; The child can
go up and down stairs with support, go up on a sofa or a bed; He looks at the
person face when embraced.
The staff suggest more
sophisticated motor opportunity and cognitive activities (symbolic play,
cause-effect game, pictures, children's books, nursery poems). These activities
need to be done on even if not clear request by the child. Our staff has a
meeting with the teacher and the school assistant; This later started to attend
every visit on the CIFRRE outpatients' clinic, by accompanying the child and
his parents.
At 4 yrs and 5 mos.:
No change in seizure's
situation. EEG: doctors speak about an improvement, but parents have not the
report.
Current drug therapy:
Carbamazepine 100 + 100 +
100.
Valproate reduced to ended.
Clobazam reduced.
Neuro-psychological
evaluation points out that the child looks at parents' face as if he is asking something.
He can play with noising toys, apparently he understands more words and
phrases, even if he doesn't follow commands.
Now he fairly coordinated
walking. He can finger feed himself, can use the fork, but cannot fill it and
he has learned to use the door handle when he wants to go out. Parents and
school assistant continue the activities at home and in school.
At 5 yrs.:
Seizures become more intense
and more frequent.
Current drug therapy:
Carbamazepine 100 + 100 +
100 mg.
Clobazam 10 mg, 1/2 + 1/2 + 1
tabs.
Lorazepam 0.5 mg.
In this period the child
had great physical and psychic discomfort. A severe ear infection, not early
detected, led to severe insomnia, with crying at night. This state lasted six
months and had its diagnosis as "ear's infection syndrome." During
hospitalization the CPK-enzyme was found at the above average level of 2020.
The child shows more
stereotyped behaviour; He has less relational behaviour, and a high
hyperactivity. Motor functions improved instead and the child began to run. The
staff suggest to parents to continue cognitive activities.
At 5 yrs. and 7 mos.:
Seizure's situation: Two
major seizures at night and at awakening, and 5-6 absences during the day. In
this period generalized tremors went along with absences, so the pediatrist
suggested using vigabatrin and stop clobazam.
Parents did no get the EEG
report.
Current drug therapy:
Carbamazepine 100 + 100 +
200 mg.
Clobazam 10 mg.
Vigabatrin 500 + 500 mg.
Any improvement came out,
but worsening in hyperactivity.
At 6 yrs. and 4 mos.:
Seizures have not changed
in frequency, but a new type of seizure emerges very similar to those flexion
spasms the child had in early age. He turns the head to left, has generalized
tremor and repetitive groaning.
Parents did not have the
EEG report, but they refer about worsening in terms of increased discharges.
Many pharmacological
attempts took place by discontinuing and reintroducing the same drugs, by
increasing vigabatrin till the current drug therapy:
Vigabatrin 750 + 750 mg.
Carbamazepine 100 + 100 mg.
Parents complained that the
child was more nervous and more irritable. He cannot sit at the table at
mealtime, have compulsive behaviour of putting in mouth objects and his hands.
He doesn't want to sleep alone, and wake up often during night.
The staff and the family
decide to maintain the child in kindergarten for next year, instead of starting
elementary school.
At 7 yrs. and 2 mos.:
Parents look very
discouraged because too many seizures. Those poorly decreased in frequency, but
are more severe and generalized. Some aversive seizures emerge, about 4 per
day.
Parents decide to change
medical advice and start a pharmacological therapy with one of us.
Neuro-psychological
evaluation put in evidence hyperactivity, stereotypies involving hands and
rocking. This later is often associated with one crying episode. The child has
night sleeping very troubled and has also bruxism.
Current drug therapy:
Vigabatrin reduced to
ended.
Introduction of Diazepam and
Pyridoxine.
Carbamazepine 100 + 100 + 100
mg.
Amantadine 50 mg.
At 7 yrs. and 6 mos.:
The boy had one less
intense seizure per day along with fewer aversive seizures (2-3 per day). Now
he is more calm, but stereotypies had no change. The understanding of language
is better and the child starts to follow simple commands ("come here and
show me the picture," "pick up the towel"). He can discriminate
knowing pictures, sorting between two. He completes toilet training during the
day. Sleeping is better.
The staff push the
cognitive activities, using structured didactic aids, looking for an
integration in elementary school next year.
To current drug therapy it
was added:
l-glutamine 125 mg.
At 7 yrs and 10 mos.:
One major seizure per day,
rare aversive seizures take place. EEG: Fewer slow waves.The environmental
participation is better, there is no more hyperactivity, stereotypies show no
change in their features, but less in intensity and duration. Sleeping is
almost normal, with no more awakening during night. Now the child starts to
attend first grade of elementary school, with the continuity of school
assistant. Our staff suggest introducing Facilitated Communication.
Current drug therapy, as
daily doses:
Carbamazepine 600 mg.
l-glutamine 250 mg.
Amantadine 100 mg.
Pyridoxine 150 mg.
Delorazepam 1 mg.
At 8 yrs and 6 mos.:
Parents have ceased the
drug therapy for one month, and the child was more pale and showed more
bruxism. So they started it again. Now he is less repetitive and more
attentive. He had 3 seizures during the whole period, at awakening time.
Sometimes he cries and put hands in the mouth (selfstimulation). Health status
was fairly good. Apparently the understanding of danger filled out. He has
repetitive playing.
Changing in drug therapy:
Addition of Pivogabine 900
mg and Valproate 100 mg.
At 8 yrs. and 9 mos.:
He has more seizures and
more severe. After the seizure he falls asleep. Despite the increasing dosage
of carbamazepine (+ 100 mg at night), the child did not get any change as for
intensity and frequency of seizures. The EEG showed multifocal paroxysmal
condition, especially on the left parietal lobe. Bruxism got down with good
health status, no change in diet choosing, regular bowel function.
Psycho-cognitive evaluation
put in evidence an increased environmental participation and reactivity; he can
always follow commands. He is calmer when involved in physical and emotional
activities. On request he can match similar pictures, and discriminate
different pictures. The child improved his manual competence and he began to
colour a drawing, if helped.
He reaches complete day and
night toilet training, and goes to the bathroom door when he needs to use it.
Language has no change. The staff suggest continuing NTM stimulation and
Facilitated Communication both at home and in school.
Changing in drug therapy:
Pivogabine stopped.
Delorazepam ended.
Clonazepam 0.5 + 1 mg as
drops.
At 9 yrs and 7 mos.:
Seizures' situation: the
child present no more generalized and aversive seizures, rare absences are left
over. In the last month he used to wake up at night, and have episodes of
selfaggression, at different hours, usually once per night.
When he is on stress
condition can be calm by embracing and caressing him. Language is still absent.
In that unusual situation often he becomes hyperactive. Stereotypies increase
if he is tired.
The NMR reports: There are
no significant changes as compared to the findings of the previous CT scan.
Partially calcified lesions on ventricles walls on the posterior site of medium
cells are present bilaterally, and their diameter is 1.4 cm on left, and 1.0 cm
on right. There is a small nodule on the ventricle wall in the left ventricle
atrium, the diameter of which is just a few millimetres. In the brain
intraparenchymal site there are many lesions in right preolfactory area. The
imaging technique detected a small area of impregnation of contrast medium on
the cortical-subcortical site. It has a diameter of one cm, and can stand for
one glial cancer.
Current drug therapy:
Carbamazepine 200 + 200 +
300 mg.
l-glutamine 250 mg.
Pirydoxine 150 mg.
Amantadine 50 + 50 mg.
Clonazepam 1 + 1.5 mg as
drops.
Cognitive aspect is very
good with the mean of Facilitated Communication. The child answer to questions
typing on a PC keyboard, sometimes he sits in front of the PC to let parents
know that he has to express something. In this period he likes to try different
textures by touching objects (leaves, stones, flour, grated Parmesan cheese,
etc.). Though mental retardation is evident, autism is no more a global
symptom, but only some tracts are present.
He attends third grade of
elementary school.
Changing in drug therapy:
Amantadine 50 + 100 mg.
Fluoxetine 10 mg.
Discussion
The relationship between
tuberous sclerosis and autism isn't very close. In literature we found an
association with behaviour disorders including typical or partial autism and
attention deficit disorder (Hunt, 1995).
Reich at al., 1997,
associate Bourneville's disease with autism and suggest a diagnostic search in those
patient showing autistic symptoms. Actually this association is not a necessary
consequence of tuberous sclerosis. Out of 28 subjects diagnosed as having TS,
only 12 had symptoms leading to autism diagnosis (8 subjects) or Pervasive
Developmental Disorder (4 subjects) (Gutierrez, Smalley and Tanguay, 1998).
On the other hand, even the
relationship between epilepsy and autism, within TS, is not completely clear.
Two patients underwent brain surgery for intractable epilepsy and their
histopathological examination of brain tissue that was removed suggested a
diagnosis of TS.
They became seizures-free
and showed a dramatic improvement about autism symptoms.
However, one of them had a
relapse to his presurgical state concerning autism, with his pubertal growth
spurt, even if he remained seizures-free. Several years after the surgery, this
boy showed some improvement with respect of self-injury and aggression. He had
some improvements in other autistic symptoms than in the year preceding
epilepsy neurosurgery (Gillberg et al., 1996).
Epilepsy symptoms don't
occur with the same manifestations in TS. Epilepsy associated with TS is often
intractable, but seizure control has benefited from the introduction of the new
antiepileptic drugs.
Drug-resistant patients
carefully selected can have assessment as candidates for surgical removal of
epileptogenic lesions, by intensive monitoring. The success of epilepsy surgery
is predicated on the clear identification of epileptogenic foci (Curatolo,
1996; Gillberg et al., 1996; Di Rocco et al., 1995).
Mental retardation is
another variable aspect in TS, since it can range from moderate to very severe.
A type of seizure on initial examination like infantile spasms, is a
significant risk factor for poor mental development in patients with TS.
Age at time of first
seizure is not an independent risk factor but reflects the early ages at which
these patients have the diagnosis of infantile spasms.
Neither sex, nor history of
diphtheria, tetanus and pertussis immunization, is a risk factor for the
subsequent development of poor mental development TS patients (Jozwiak, Goodman
and Lamm, 1998).
In our case, which is yet
under treatment, apparently all these aspects (autism symptoms, seizures and
mental retardation) have benefited from the combined psychomotor and
pharmacological treatments.
Conclusions
The careful analysis of
this case lead us to consider how the beginning of a more intense psychomotor
treatment and the therapeutic relationship with a rehabilitation staff gives
the following:
* Increasing awareness in
the family about their active role in the child development, even if the
disabilities couldn't be "cured" (Crivelli and Donati, 1998);
* Faster improvements in
psychomotor skills compared with the previous period.
The beginning of a specific
pharmacological therapy combined with the above approach lead to advanced
improvements:
* Evident differences in
relational aspect and in stereotypies;
* Clear improvements in
seizures which are less intense, and show less aversive seizures.
References
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family in educational and rehabilitative programs for disabled child: which
conditions can make it working? Ital J Intellect Impair / Riv It Disturbo
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Curatolo P.: Neurological manifestations
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Printed on It. J. Intellect. Impair. 1999, 12: 31-39
Author’s address: Dr. Chiara CRIVELLI, Coop CIFFRE via M. D’Azeglio 2,
37123 VERONA (Italy).
chia.sci@iol.it
Other genetic and chromosomal anomalies
Drug modulation of stress reactions
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