DRUG THERAPY IN AICARDI-GOUTIERES SYNDROME:
By
Renato COCCHI, neurologist and medical psychologist
Abstracts.
The antistress therapy regimen used glutamine, pyridoxine, carbamazepine and bromazepam as
basic drugs. Other drugs were added as the baclofen
to reduce leg stiffness. This detailed report informs about the positive
results and leads to confirm that symptoms of stress make worse of another
genetic illness beyond its specific symptoms.
Of
course there are no doubts that the basic genetic anomaly does not have any
advantage. However, the quality of life of that girl should be less disastrous
and her fate delayed.
Key
words: Aicardi-Goutieres syndrome; girl;
stress; symptoms; drug therapy.
Other genetic and chromosomal anomalies
Mental retardation
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The Aicardi-Goutieres syndrome (AGS) is an autosomal recessive encephalopathy that causes
developmental arrest, intracerebral calcification,
and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid
interferon-alpha (IFN-alpha) (Giraud et al., 1986; Bonnemann and Meinecke, 1992; Tolmie et al., 1995; Kato et al., 1998; Faure
et al, 1999; Barth et al., 1999; Polizzi
et al., 2001). <o:p
Diagnosis
requires the presence of progressive encephalopathy with an onset shortly after
birth, and characteristic clinical neurological and neuroimaging
signs with chronic CSF lymphocytosis (Tolmie et al., 1995).
Neuroimaging showed severe and progressive brain atrophy in all
patients. The extent and intensity of the calcification were variable even in
the same sibship. CSF lymphocytosis
persisted beyond 12 months of age in seven children. High levels of
interferon-alpha were found in serum and CSF in 14 patients.
The
higher CSF levels suggest intrathecal synthesis. Tubulo-reticular inclusions related to the presence of
interferon were found in four additional children. The 19 patients still alive
(six older than 10 years) were profoundly disabled.
According to Barth et al., 1999, microangiopathy plays a significant role in the
pathogenesis of AGS.
First
months she had normal milk sucking Eyes contact with their parents was present.
The parents deny any other abnormal symptom.
Other
symptoms are: Cold hands and feet, not hunger in first
morning, spastic constipation with bad breath, lack of verbal language, noise
intolerance, drooling, sweating in the first sleep hours, daily bruxism.
13.11.1999:
She is going better. Now she sleeps regularly, does
not have sweating during sleep, does not have vomit, eats normally. She put
some weight. Her bowel activity has decidedly improved, and now she does not
have any bad breath. Her muscles' tone improved and now she starts head
muscles' control. Now she is less boring, but her language did not appear.
Bruxism nearly went out but drooling did not have any
improvement, and the same for noise standing up. Her motion progressed. Teachers
of her school found her improved, and there she eats nearly all school lunch.
11.01.2000:
The parents said she was going worse. Some stomach problems came out again. She
got newly hard constipation. Sometimes she awoke during the night, but only
once. Her feet became less cold. The bruxism
reappeared. Muscles show more stiffness.
She
stands better the noise up. Last days she is having more drooling. The previous
bad breath reappeared. Her head control became poor again. The school makes her
more tired. In spit of all it, her mood is fairly good.
11.11.2000:
She was well, with scarce or null problems of stomach, reduced constipation and
reduced bad breath. Reduced muscles' stiffness leads to better doing
rehabilitation therapy. Her chewing is going better although even poor, and now
she eats everything. Even in school teachers found her improved, where she
looks less tired. Sleeping is going well, and she is falling asleep by alone in
the evening.
Some days
his drooling is very evident, but bruxism came down.
Her feet are cold again. She does not stand up noise, to which reacts with a
powerful startle-reflex. Her head control seems improved. Now she started using
facilitate communication.
Now she
is more serene, more attentive, more affectionate but
a little clinging.
03.03.2001:
She is going well. The vomit fully ceased. Only in fewer moments she has bad
breath. Muscle stiffness did non vary. Her hands are
more mobile. Being lesser dystonic, she better stands
up the rehabilitation therapy.
There is
always some difficulty in engulfing liquid foods. Bruxism
rarely appears, but drooling has some worse days, perhaps lesser than in past.
The startle reflex in response to noise came down. The head control is going
better, although not even complete.
06.10.2001:
In summer she had a neurological examination at the
The vomit
did no reappear. Her stiffness came down. She is more attentive and noting what
happens around her. She eats more and chews more. With the facilitated communication
she can eat by herself. She tastes new foods. There is less difficulty in
engulfing liquid foods. When she is thirsty, she uses to signal it, and says
"ahm" when she wants to eat.
Bad
breath is a rare event, like bruxism. Drooling did
not modify, with days where is very intensive.
She was
healthy, with no putting other weight, but she became soundly taller. Her
teachers said that they might work longer with her.
06.04.2002. These
last few days she has suffered weather. Altogether she goes well, she is grown,
and she is more serene and gladdens, with less angry fits. Her drooling did not
change as first. Now, she is even less rigid. Her use of right hand improved.
To lie in bed is good.
She says " mama ", and points up both hunger and thirst.
The appetite is
very good, she chews better and the diet is increased, her bad breath is always
less present. She tries to eat by herself, but at home she has no much in it.
The swallowing of the liquids improved. The bruxism
is notably reduced.
05.10.2002. Still some
improvements appeared. She is grown. They start to appear the secondary
features of her sexual development. As for the language, she says
"mama" and tries to speak more. She understands more and wants more
to talk. She becomes angry with greater facility. The stiffness of her muscles
is unchanged, but not regressed. The school year went better, with increased
learning ability by improved attention. Now she chews more and can drink
better.
Rarely she has bad breath. When eating, she does more use of her
right hand, but even in other circumstances. No more present the bruxism. The startle reflex to the noises comes out even.
Good the control of the head, even if there is a trend to flexing it. Sitting
position not yet got. As for health, she did well. At school she tries to eat
by herself. When in her bed, if she needs to turning, she calls to be helped.
The face
is less pale. In last months she was more drooling, because she suffers the
weather and the summer season was pity.
Current therapy
(daily doses ):
07.06.2003.
A further checkup.
Drooling decreased very much. Now she has spastic
constipation. She holds her head enough sustained, much more than she did in
the preceding checkup. Smiling appears frequently.
Her breast developed, but she did not start menses. Language nearly without any
progress, as for its production, but she uses better what she knows.
Understanding still improved, and at school her teachers understand better her.
No temper
tantrums reported as in pass. According to her mother, stiffness of limbs did
not change. Her attention improved and she works better with the computer. Her
chewing did not improve. She does new noises with her mouth. She drinks aver
few, but her swallowing does not make problems. Lately bad breath reappeared.
She
cannot use the left hand but now she uses the right hand with increased
difficulty. Rare night bruxism reappeared. The
startle reflex did not show any modification. Sitting position is not achieved.
By now, She has hip dislocation problems on her left
side. At school they feed her, and the same does her mother, to spare time.
During
the night she calls if she needs to be turned. The mother says that she did not
is not regress, but springtime stress might have had some bad action
(constipation, bruxism).
Therapeutic
variation: Baclofen 7.5mg for twice a day, by the
oral via; Carbamazepine 150mg twice a day by the oral
via.
First ten
days of December 2003: The ninth checkup. As for the
parents she did not regress, excluding the problem of the hip. Generally she is
doing enough well. The last August her menses started.
Motility; The left leg
shows a dislocated hip. The femur's dislocation worsened. When she has pain,
she keeps his leg in bending. This pain could come out from muscular cramps.
The control of her head did non change. As first, she has difficulties when she
uses her right hand. The sitting position did not come.
Language: The comprehension
improved. Perhaps her language improved a little. She produces new sounds with
her mouth. There is an evident pronunciation of the "p", while first
it was always "b". At school they understand her well. Some time she
gets angry, when people do not understand her.
Learning: Her attention is
more than sufficient, and she watches little the television. To use the
computer gives her some difficulties.
Symptoms
of stress: She felt bad of the change of the season. The drooling first reduced,
but now it is little increased. She has had a moment of intestinal spasms, with
goatlike faeces, but now she is doing better. Some
daily bruxism occurred. The reflex of fear happened
as previously. 1-2 times fo
night, she calls, to have her side turned.
Feeding: Chewing does not work better. Perhaps she can drink
better. Halitosis disappeared. At school she is sppon-feeded,
to do quickly.
Mood: Habitually, she
is happy, but not when the leg gives pain to her.
Therapeutic
variation (daily doses, by the oral via): Baclofen
20mg; Bromazepam 0.8mg.
First ten
days of October 2004: The tenth checkup, with current
drug therapy since 61 months. The SAMe
has been hung by her mother. As for the parents, she is doing enough well.
Motility: She has given the
surgical operation to reducing the left hip dislocation, and she stood it well.
From a physical point of view, she worsened: Now she has her motility reduced.
Some times he shows stiff. The head control is discreet, but there is always
left side laterality. Preferentially, she uses the right hand. The sitting
position did not improve. She better bears the pain of the posture, and so she
used to sleep only on one side.
Language: Language did not
change, but the comprehension improved. Always difficulty occurs when she has
to pronounce the "p".
Learning: After summer
holidays, the teachers found her well. She is attending the school, but that
tires her. The attention is stable. The use of the computer is always
labouring.
Symptoms
of stress: When she feels the weather change, she becomes boring. Nighttime bruxism decreased. The
startle reflex did not modify itself. Drooling decreased. The halitosis did not
come back. She spends much time without urinate, even till five hours. She is
ever constipated, of the spastic type. Problems of stomach did not reappear and
so, she has regained bodily weight. During the night, she has less called for
changing her position.
Usually,
she wakes well up, about a quarter to eight.
Feeding:
She
chews better, but she is slower in eating. She does more noise with her mouth.
Now, she doesn't drink more, but she can better do it. Diet is more varied, but
now she refuses bananas, while she likes khakis.
Mood: Not significant
variations occurred.
Therapeutic
variation(daily doses, by the oral via): Creatine 1g.
Third ten
days of June 2005: The twelfth checkup, during
treatment with drugs since 69 months. She goes so and so, as for her the
parents. Probably it has started some regression, if it is not seasonal
regression.
Motility: No positive
variations reported. She has become more hypertonic. She has kept the control
of the head, even turned to the right side. The postural nighttime
pain did not vary. Now, she sleeps on both sides.
Language: The language did
not progress, but its comprehension improved.
Learning: In the classroom
she shows a little tired. Without taking the morning carbamazepine
she had fewer moments of being a doze one.
Symptoms
of stress: The daily bruxism restarted and the nighttime bruxism increased. The
drooling came out again. She has disturbed sleep and is awaking from one to
five times every night. Constipation is her usual state.
Feeding: She does labour
in eating and there are problems of swallowing. Chewing did not progress.
Sometimes she eats slowly, but she drinks some more. Every 5-6 now she
urinates. She is not thinner neither grown on weight.
Mood: In the morning she
is nervous and boring.
Therapeutic
variation (daily doses, by the oral via): Carbamazepine
200mg; Baclofen 25mg; Bromazepam
1mg; niaprazine 10mg.
First ten
days of February 2008, the fourteenth checkup.
As for her parents, she
is going not badly.
Symptoms of stress: She has restarted to do bruxism. Drooling occurs mainly when the weather changes. The frequency of the mouth ulcers
worsened. Cold hands and feet disappeared.
Motility: Spastics in bending
increased in the superior limbs. Now, she has less
pain in the legs.
Language: She would
speak.
Learning: At
school she goes enough well;
She makes herself understood and attends it gladly.
Feeding, sleep and
sphincteral control; She is eating any
food, and does less in a hurry. After she had a pharyngitis-tracheitis with a heavy cough, since
then it happens
their foods go the wrong way.
Sometimes she bites the teaspoon
and turns her head on a side.
She increased her weight. In the evening she
drinks much. Her waking up is happy, and she has not nocturia. During the day she
can keep her urine for a longer time. Even now, she
is still constipated.
Behaviour : Even at
home she strives more to do
herself understood. Now, she bears
well of being touched.
Therapeutic variation (daily
doses, by the oral via): S-Adenosil-l-methionine
100mg; Glutamine 125mg; Carbamazepine 500mg.
Discussion.
"However, the syndrome may be present with individual variations in
severity, rapidity of evolution, and imaging features."
The first
is that subjects' symptoms vary because they have different adjunctive troubles
of loci, although owning a common genetic base. The second is that in each
affected case that illness elicits also symptoms of stress to which each body
answers along with its constitutional - ie. Genetic and acquired - ability to cope with stress. This
second one is simpler, according to the Occam's
razor.
Not only so, but it is a general feature, being non specific of AGS. It is
always the same that allows to afford different
genetic abnormalities showing individual variations, by using drugs. Of course,
we can treat only symptoms of stress, but often these symptoms are very
impairing, beyond the specific genetic outcome. Following these criteria,
already reported in my home page, since 23 years I am treating Down syndrome persons by drugs, but also Tuberous Sclerosis, Cri-du-chat and Smith-Magenis syndromes.
So I do
not know if clinical improvements I gained have some counterpart in slowing or
stopping the fatal progress of the leukodystrophy. If
so, the present case should be the third one after the two reported by Polizzi et al., 2001.
Barth PG; Walter A; van Gelderen I. Aicardi-Goutieres syndrome: a genetic microangiopathy?
Acta Neuropathol (Berl) 1999, 98:212-216.
Kato M;
Ishii R; Honma A; Ikeda H; Hayasaka
K Brainstem lesion in Aicardi-Goutieres syndrome. Pediatr Neurol 1998, 19:145-147.
Polizzi A; Pavone P; Parano E; Incorpora
G; Ruggieri M. Lack of progression of brain atrophy in Aicardi-Goutieres syndrome. Pediatr Neurol 2001, 24: 300-302.
Tolmie JL; Shillito P; Hughes-Benzie R;
Stephenson JB. The Aicardi-Goutieres
syndrome (familial, early onset encephalopathy with calcifications of the basal
ganglia and chronic cerebrospinal fluid lymphocytosis).
J Med Genet 1995, 32:881-884.
Author's address: dr Renato Cocchi, via Rabbeno, 3
42100 Reggio Emilia (Italy)
renatococchi@libero.it
Mental retardation
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