DROOLING (OR SIALORRHEA)
IN DOWNS TREATED WITH PRIMARILY ANTISTRESS DRUGS.
Renato COCCHI, a neurologist and a medical
psychologist.
Summary.
An aspecific therapy with antistress drugs
lasting 10.67 +/- 4.18 months average, drove to the disappearance of drooling
(sialorrhea) in 49 out 51 Down subjects (24 F and 27 M; M/F ratio = 112.5;
Average age at the first consultation: 75.73 +/- 60.60 months, with 6-279
months range; normal distribution of the chromosomal anomalies).
As an aspecific symptom of stress, drooling
finds in many full different illnesses.
It suggests the drooling as creditable to
the fact that the stress can induce hypothalamic glutamergic-GABAergic
unbalance, with hyperfunction of the hypothalamic neurons controlling the vagal
nuclei that become overstimulated.
Key words: Down syndrome, drooling, stress,
therapy, antistress drugs.
Drug modulation of stress reactions
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The first epidemiological investigation on
the sialorrhea symptom in a consecutive series of 510 subjects with Down
syndrome, from which autistic subjects or with other Pervasive Development
Disorders excluded (Cocchi, 2004). Part of them who got drug therapies, with
the disappearance of this symptom, had a specific investigation.
It deserves to remember that the innervation
controlling the salivary flow belongs to the vegetative nervous system, and
primarily to the parasympathetic system. It may add even a sympathetic
stimulation that however would not have an antagonist, but synergistic action,
with an increase of the saliva amount.
Materials and methods
This new investigation used 103 clinical
cards related to Down Ss living in family and seen by the author, in
outpatients'. In all sialorrhea was reported during the first visit.
From every card I collected:
- gender;
- chromosomal diagnosis; -
- age at 1st consultation;
- disappearance of the sialorrhea;
- months of drug therapy till such an event;
- drugs under way at the last checkup.
I statistically elaborated the data so
obtained for gender, chromosomal anomaly, age at 1st consultation, age bands,
length of the therapy, used drugs, and I evaluated them, when possible, with
the Chi Square test, the linear regression and the correlation.
Results.
The symptom was present in 20.20% of the
whole series, and much probably this is the exact rate, because almost
certainly the not investigated Ss (?) were without it. If they had shown
sialorrhea at the first consultation, or at the first checkup, I had surely
observed it. On the other hand, being a symptom that disturbs the parents, they
would have attracted my attention on it, if I had missed it.
Tab. 1: Epidemiological data of the group of
subjects with sialorrhea.
|
|
No. of Ss |
% |
|
Presence of the symptom |
103 |
100.00 |
|
Males |
59 |
57.28 |
|
Females |
43 |
42.72 |
|
M/F ratio |
|
137.21 |
|
|
|
|
|
Chromosomal diagnosis |
|
|
|
Standard trisomia 21 |
92 |
89.32 |
|
Traslocations |
4 |
3.88 |
|
Mosaicisms |
1 |
0.97 |
|
Only clinical diagnosis |
6 |
5.83 |
|
|
|
|
|
Average age at 1st visit (months) |
88.67 +/- 65.54 |
|
|
Range (months) |
6-308 |
|
The usual male prevalence rests, even if it is
slightly greater of what found at the birth for Italian children (Camera and
Mastroiacovo, 1984).
The distribution of the chromosomal
anomalies parallels what known for Italian and international Down populations.
The average age at the first visit is higher
of than that of the whole series of 510 Ss (Cocchi 2004), but the age range is
more narrow.
To note, even in a subject with more of
twenty-five years (308 months) had this symptom.
Tab. 2: The drug treated group:
Epidemiological data.
|
|
No. of Ss |
% |
|
Drug treated Ss |
51 |
100.00 |
|
F |
24 |
45.28 |
|
M |
27 |
54.72 |
|
M/F ratio |
|
112.5 |
|
|
|
|
|
Chromosomal diagnosis |
|
|
|
Standard trisomy 21 |
47 |
92.16 |
|
Traslocations |
3 |
5.88 |
|
Only clinical diagnosis |
1 |
1.96 |
|
|
|
|
|
Average age at 1st visit (months) |
75.73 +/- 60.60 |
|
|
Range (months) |
6 - 279 |
|
In this group the M/F ratio, too maintaining
the male majority, is already less prevailing than that of the whole group of the
subjects with sialorrhea. The distribution of the chromosomal diagnosis, with
lack of Ss with translocations, may be a casual fact and creditable to the
modest number of this subsample.
Tab 3. Results on the symptom
"sialorrhea".
|
|
No. of Ss |
% |
|
Drug treated Ss |
51 |
100.00 |
|
Disappearance |
49 |
96.08 |
|
Rarely present (*) |
1 |
1.96 |
|
Not varied (**) |
1 |
1.96 |
|
Therapy length in 49 Ss |
10.67 +/- 4.18 mesi |
|
|
Range |
4-24 mesi |
|
(*) A child of thirty-seven
months at the first visit, treated for twelve months.
(**) A person of 279 months
at the first visit, treated for thirty-five months.
The therapy seems has acted much positively
on this symptom, but in two cases it failed in removing it.
Tab. 4: Used drugs under way at the last
checkup, in mg/daily, if not otherwise specified.
|
Active compounds |
Ss No. |
%s |
|
|
||
|
Alphachetoglutarate of pyridoxine 300-600 (*) |
3 |
5.88 |
|
Alphtocopherole 50-100 |
5 |
9.80 |
|
Biotine 2.5.5 |
5 |
9.80 |
|
Bromazepan 1-2.5 |
3 |
5.88 |
|
Carbamazepine 50-200 |
14 |
27.45 |
|
Delorazepam 0.2-0.5 |
4 |
7.84 |
|
Deanol emisuccinate 1000-2000 |
4 |
7.84 |
|
Diazepam 1-3 |
40 |
78.43 |
|
5-hydroxitriptophano 25-50 |
7 |
13.73 |
|
l-glutammine 125-250 |
43 |
84.31 |
|
Glutammine + pemoline (45+5) -(90+10) (*) (**) |
9 |
13.73 |
|
Metiltetrahydrofolates 7.5 |
46 |
90.20 |
|
Nicotinamide 50-100 |
5 |
9.80 |
|
Oxazepam 5-10 |
6 |
11.76 |
|
Pantotenate 150-300 |
4 |
7.84 |
|
Pyridoxine 75-150 |
44 |
86.27 |
|
Pyritinol 50-100 (*) |
11 |
21.57 |
|
s-adenosil-l-metionina 100-200 |
10 |
19.60 |
|
Thiamine + pyridoxin + cyanocobalamine 125mg + 125mg + 250 gamma |
4 |
7.84 |
|
Viloxazine 25-100 |
3 |
5.88 |
|
|
||
|
Total drugs under way |
269 |
|
|
Total drugs in each person (average) |
5.27 |
|
(*) Not more marketed in
Italy; (**) Prescribed in hyperkinetic Down subjects.
Tab. 5: Subjects with sialorrhea who did not
come back for the checkup.
|
|
No. of Ss |
% |
|
Ss who did not come back |
52 |
100.00 |
|
F |
20 |
38.56 |
|
M |
32 |
61.44 |
|
M/F ratio |
|
160 |
|
|
|
|
|
|
|
|
|
Chromosomal diagnosis |
45 |
86.53 |
|
Standard trisomy 21 |
1 |
1.92 |
|
Traslocations |
5 |
9.62 |
|
Only clinical diagnosis |
1 |
1.92 |
|
|
|
|
|
Average age at 1st visit (months) |
101.37 +/- 67.67 |
|
|
Range (months) |
12 - 308 |
|
Since the choice of avoiding the checkup,
and then of starting not the therapy, depended from the parents as a single couple,
we can accept this fact as casual, if we exclude the greater presence of
subjects with only clinical diagnosis. Surely they were the more aged Ss, born
when the chromosomal diagnosis was not usual. In fact, the average age at the
first visit is about twenty-five months higher than that of the treated
subsample, and the top limit of these ages was similarly higher.
Tab. 6: Comparison by age bands, between the
group treated Ss ( age to the treatment end) and that of subjects who did not
come back for checkup (age at the first visit).
|
Age band (months) |
Drug treated Ssi |
% |
Not treated Ss |
% |
|
1-12 |
1 |
1.96 |
1 |
1.92 |
|
13-24 |
4 |
7.84 |
6 |
11.54 |
|
25-36 |
4 |
7.84 |
6 |
11.54 |
|
37-48 |
8 |
15.69 |
1 |
1.92 |
|
49-60 |
5 |
9.80 |
5 |
9.62 |
|
61-72 |
2 |
3.92 |
1 |
1.92 |
|
73-84 |
3 |
5.88 |
2 |
3.85 |
|
85-96 |
3 |
5.88 |
2 |
3.85 |
|
97-108 |
3 |
5.88 |
3 |
5.77 |
|
109-120 |
3 |
5.88 |
6 |
11.54 |
|
121-132 |
2 |
3.92 |
3 |
5.77 |
|
133-144 |
3 |
5.88 |
3 |
5.77 |
|
145-156 |
2 |
3.92 |
3 |
5.77 |
|
157-168 |
2 |
3.92 |
2 |
3.85 |
|
169-180 |
1 |
1.96 |
2 |
3.85 |
|
181-192 |
1 |
1.96 |
3 |
5.77 |
|
193-204 |
0 |
0.00 |
0 |
0.00 |
|
205-216 |
0 |
0.00 |
0 |
0.00 |
|
217-228 |
0 |
0.00 |
0 |
0.00 |
|
229-240 |
2 |
3.92 |
0 |
0.00 |
|
241+ |
2 |
3.92 |
3 |
5.77 |
|
Totali |
51 |
100.00 |
52 |
100.00 |
Chi Square = 442.315 with 20
df and p < 0.0009
With much high statistic probability, the
two groups belong to two different populations, then it is a great deal probable
that the antistress drug therapy acted on the sialorrhea.
Tab. 7. Comparison between the age at the
first visit and length of the therapy (in months) in the forty-nine Ss with
disappearance of the symptom.
|
!st visit age |
48 |
45 |
44 |
8 |
41 |
160 |
172 |
145 |
106 |
70 |
125 |
17 |
14 |
|
Ther. length |
4 |
4 |
4 |
4 |
6 |
6 |
6 |
6 |
6 |
7 |
8 |
8 |
8 |
|
|
|||||||||||||
|
!st visit age |
98 |
104 |
30 |
53 |
110 |
17 |
36 |
113 |
59 |
58 |
34 |
12 |
97 |
|
Ther. length |
8 |
8 |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
10 |
10 |
10 |
11 |
|
|
|||||||||||||
|
!st visit age |
138 |
131 |
43 |
113 |
119 |
128 |
6 |
149 |
86 |
79 |
69 |
14 |
243 |
|
Ther. length |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
13 |
13 |
14 |
|
|
|||||||||||||
|
!st visit age |
6 |
25 |
74 |
37 |
27 |
73 |
36 |
16 |
23 |
|
|||
|
Ther. length |
15 |
15 |
16 |
16 |
16 |
17 |
17 |
19 |
24 |
||||
Linear regression and correlation.:
no.
49; b = -0.01; a = 11.43; SEb: 0.01; SEa: 1.01; Estim SE: 4.20 (For the linear regression no interpolation line found).
r
= -0.138; t = -0.953, with 47 dfl and p = 0.346 NS.(The correlation does not significanly differ from 0).
The length of the drug therapy, till the
disappearance of the symptom, does not correlate with the age.
Discussion.
Like I already remembered, in my preceding
article (Cocchi, 2004 ) drooling also impairs socially the sufferers and
isolation is unfortunately frequent because saliva soils furniture, carpets,
toys, and the clothing of peers, siblings, parents, relatives and caregivers.
Although the problem of the oversalivation
with drooling in Down syndrome subjects is well known, to my knowledge
(research with Google, and on Medline since the 1960 key words: sialorrhea,
oversalivation, drooling, Down syndrome) there is not any epidemiological
survey on this symptom. What I did (Cocchi, 2004) is, now, the only one.
The oversalivation with drooling is an
aspecific symptom found in persons suffering from full different illnesses
among which mentally retarded, with or without basic genetics, psychotics and
others even apparently normal, beyond as side effect of psychodrugs therapies
(Cocchi, 2004).
The sialorrhea cannot be then a symptom that
directly depends on the trisomy 21. Otherwise, all Downs would show it.
Moreover, as for my personal experience too, we find it also in other
chromosomal or genetic anomalies (see later on).
The prevalence found in the series of 510
Down persons (Cocchi, 2004) was about one out of five (20.20%). It had a
statistical significant correlation with the age, in the sense that it went
down with the age went up, however without full disappear. It is possible even
that such a correlation becomes less hold or even disappear during the older
age. Now, it is common evidence that some elderly persons start to drooling,
even if they never did it previously.
In the preceding investigation I thought it
possible that the sialorrhea was a symptom of metabolic internal stress, with limited
area parasympathetic activation by the brain (Cocchi, 2004).
Following this second research, I reinstate
this first hypothesis but I believe in a more complex relationship.
The primarily antistress therapy prescribed
by me, too having significantly led to the disappearance of the symptom in over
than 96% of so treated subjects, did not work in two cases. On them we could
think:
1. The prescription was not suitable for
both cases;
or, 2. They took the therapy for not enough
time;
or, 3. The sialorrhea is a stress symptom,
but it is only such by an indirect pathway.
The inverse relationship with the age grows,
even if very narrow (Cocchi, 2004), is not absolute neither in juvenile, nor
early adult age.
It remembers, for analogy, the time course
of the bedwetting, which in the nearly all the cases, disappears with the
puberty, but this is not always true. Being a bedwetting person, it causes
unfitness to the military service in Italy, because otherwise the carrier would
become the laughingstock of all the fellow soldiers, with heavy
psychological-relational following.
Both the sialorrhea and the bedwetting can
reappear, or appear for the first time, in the senile age.
As for a drug therapy, the anticholinergic
drugs found room, owing to the parasympathetic prevalence of the symptom, since
the parasympathetic system has the acetylcholine as its neurotransmitter.
The more studied drugs are the benztropine,
the saltropine, the glycopyrolate, and the scopolamine. Their effectiveness on
the sialorrhea is much variable and unpredictable, and it does not overcome 45%
of so treated persons. The anticholinergic drug acts by inhibiting the saliva
secretion through a reversible stop of controlling cholinergic receptors. Side
effects like dry mouth, iris dilation, dark vision, urine retention,
constipation, delirium and disorientation were reported, leading to the need to
stop the therapy (Leung and Kao, 1999).
There is not literature on links between
sialorrhea and stress, if not for the fact that it produces stress. The
antistress drug therapy here set up did not have the sialorrhea as a specific
target, and, as for Down syndrome, it grounds on what written in Cocchi, 1993,
and, generally, on the theoretical bases I explicated in Cocchi 2003.
Over than on the sialorrhea in the
Down syndrome, the antistress drug therapy acted favourably on the sialorrhea
in cases of: the Cri-du-chat syndrome ( Cocchi, 2001 ), syndrome of Aicardi
Goutieres (Cocchi, 2002 ), partial trisomy of the chromosome 22 (Cocchi, 2003
), GM1 gangliosidosis (Cocchi, 2003 ), and on a mental retardation with
microgiry, of which it was not found any genetic base (Cocchi, 2002).
The sialorrhea could be because the stress
can produce GABAergic-glutamergic hypothalamic unbalance. By that it drives to
an overfunction of hypothalamic pathways controlling the vagal nuclei (mainly
the ambiguous nucleus, where even the glossopharyngeal nerve originates) which
become overstimulated. An antistress drug therapy seems, at least to a large
extent, able to bring this mechanism to a better operation.
Conclusions.
An aspecific therapy with antistress drugs,
drove to the disappearance of drooling (sialorrhea) in 49 out 51 Down subjects
so treated.
As an aspecific symptom of stress, drooling
finds in many full different illnesses.
It suggests the drooling as creditable to
the fact that the stress can induce hypothalamic glutamergic-GABAergic
unbalance, with hyperfunction of the hypothalamic neurons controlling the vagal
nuclei that become overstimulated.
References.
Cocchi R. Drug therapy
in Down's syndrome: A theoretical context . It. J. Intellect. Impair. 1993, 6:
143-154.
Cocchi R. Primi mesi di farmacoterapia in un
caso di sindrome di Cri-du-chat..November
2001.<www.stress-cocchi.net/genetics3-it.htm>
Cocchi R. Terapia con
farmaci in una sindrome di Aicardi-Goutieres: Resoconto di 51 mesi di
trattamento Aprile 2002. <www.stress-cocchi.net/Genetics5.htm>
Cocchi R. Un bambino flaccido con microgiria e
ritardo mentale. Resoconto dei primi 19 mesi di trattamento con farmaci. Giugno
2002. <www.stress-cocchi.net/mentret4.htm>
Cocchi R Ventisette mesi
di farmacoterapia antistress in un caso di trisomia parziale del cromosoma 22.
Aprile 2003. <www.stress-cocchi.net/genetics7.htm>
Cocchi R. Trattamento
con farmaci antistress di una gangliosidosi GM1, di probabile tipo intermedio
giovanile-adulto. Luglio 2003. <www.stress-cocchi.net/genetics9.htm>
Cocchi R. La
scialorrea (o perdita di saliva) nei Down. Indagine epidemiologica su 510
soggetti. Gennaio 2004 <www.stress-cocchi.net/Down38.htm>
Cocchi R. Occorrera'
recuperare la nozione clinica di "terreno individuale"? Lo
Spallanzani. 2003, 17: 19-22.
<www.stress-cocchi.net/Speculation4.htm>.
Leung AKC., Kao CP. Drooling
in children. Pediatrics and Child Health 1999, 4: 405-411.
Posted on Internet on March 2004.
Copyright by Renato Cocchi 2004.
Author's address: dr Renato
Cocchi, via Rabbeno, 3
42100 Reggio Emilia
renatococchi@libero.it
Drug modulation of stress reactions
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