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S61

1. Associate professor, Universidade Federal do Rio Grande do Sul (UFRGS).


Coordinator of the Programa de Dficit de Ateno/Hiperatividade
(PRODAH), Hospital de Clnicas de Porto Alegre (HCPA), Porto Alegre,
RS, Brazil.
2. Associate professor, Fundao Faculdade Federal de Cincias Mdicas
de Porto Alegre (FFFCMPA) and Universidade Luterana do Brasil
(ULBRA). Specialist in Development and Behavior, Center for Development
and Learning, University of North Carolina at Chapel Hill.
Financial support: This study was carried out with partial support from
Fundo de Incentivo a Pesquisa (FIPE) of Hospital de Clnicas de Porto
Alegre and from CNPq.
Abstract
Objectives: To descrlbe the maln aspects of attentlon deflclt/hyperactlvlty dlsorder, lncludlng hlstory, epldemlology,
etlology, neuroblology, cllnlcal features, comorbldltles, dlagnosls, outcome and treatment.
Sources of data: Comprehenslve, non-systematlc revlew of the llterature on attentlon deflclt/hyperactlvlty
dlsorder.
Summary of the findings: Attentlon deflclt/hyperactlvlty dlsorder has a neuroblologlcal basls, and ls hlghly
prevalent ln chlldren and adolescents. Treatment ls very efflcaclous, lncludlng the use of medlcatlon ln most the cases.
Conclusions: Pedlatrlclans are ln a prlvlleged posltlon to detect thls dlsorder early and to start the lnltlal
management of less severe cases and of those not compllcated by extenslve comorbldltles.
J Pediatr (Rio J). 2004;80(2 Suppl):S61-S70: Attentlon deflclt hyperactlvlty dlsorder, hyperklnetlc dlsorder, ADHD.
Recent advances on
attention deficit/hyperactivity disorder
Luis A. Rohde
1
, Ricardo Halpern
2
0021-7557/04/80-02-Suppl/S61
Jornal de Pediatria
Copyright 2004 by Sociedade Brasileira de Pediatria
History and epidemiology
The flrst references to hyperactlvlty and attentlon
deflclt ln the non-medlcal llterature date back to the
mld-19th century.
1
The dlsorder was flrst descrlbed ln
Lancet by pedlatrlclan George Stlll ln 1902.
2
However,
the nomenclature of thls dlsorder has contlnually
changed. In the 1940s, lt was called mlnlmal braln
lnjury, whlch was replaced wlth mlnlmal braln dysfunctlon
ln 1962, as flndlngs were more assoclated wlth
dysfunctlons of neural pathways than wlth lnjury to
them.
3
The classlflcatlon system used ln psychlatry,
ICD-10
4
and DSM-IV,
5
share more slmllarltles than
dlfferences regardlng dlagnostlc guldellnes, although
they use a dlfferent nomenclature (attentlon deflclt
hyperactlvlty dlsorder ln the DSM-IV and hyperklnetlc
dlsorders ln ICD-10).
The prevalence of thls dlsorder has been lnvestlgated
ln several countrles and ln all contlnents. The dlfferences
found ln prevalence rates have more to do wlth the
methodology used (type of sample, study deslgn, source
of lnformatlon, age, dlagnostlc crlterla, or how they are
applled) than wlth transcultural dlagnostlc dlfferences.
6,7
Therefore, natlonal and lnternatlonal studles that use
the DSM-IV crlterla tend to flnd prevalence rates of
around 3-6% ln school-aged chlldren.
6,8
A detalled
revlew on thls toplc can be found ln Faraone et al.
8
The male/female ratlo ranges from 2:1 ln populatlon-
based studles to 9:1 ln cllnlcal trlals. Thls dlfference ln
prevalence rates may be probably due to the fact that glrls
have ADHD wlth a hlgher predomlnance of lnattentlon and
fewer comorbld symptoms of conduct dlsorder, causlng
less trouble to the famlly and at school, resultlng therefore
REVIEW ARTICLE
S62 Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004
ln fewer referrals to treatment. Studles that assess
prevalence accordlng to socloeconomlc level lncludlng not
only Caucaslan patlents are rare and often yleld lnconcluslve
results.
9
Etiology
Desplte the large number of studles, the preclse
causes of ADHD remaln unknown. However, the lnfluence
of genetlc and envlronmental factors has been wldely
accepted ln the llterature.
10
Genetlc contrlbutlon ls
substantlal; as wlth most psychlatrlc dlsorders, several
genes wlth llttle effect are belleved to be responslble for
genetlc vulnerablllty (or susceptlblllty) to the dlsorder, ln
addltlon to dlfferent envlronmental factors. Thls way, the
development and progresslon of ADHD ln an lndlvldual
seems to depend on whlch susceptlblllty genes are lnvolved,
on how much each of them contrlbutes to the dlsease and
on the lnteractlon of these genes between themselves and
wlth the envlronment.
11
Although ADHD ls characterlzed by symptoms of
lnattentlon, hyperactlvlty and lmpulslvlty, lt ls qulte a
heterogeneous dlsease, at least at the phenotyplcal
l evel . Probabl y, dl f f erent cases wl t h specl al
phenomenology (cllnlcal heterogenelty) also have
etlologlcal heterogenelty. For further detalls on the
etlology of ADHD, see Roman et al.
12
Environmental factors
Psychosoclal agents that act on the chllds adaptlve
functlonlng and general emotlonal health, such as famlly
dlsagreements and presence of mental dlsorders ln elther
parent, seem to play an lmportant role ln the development
and perslstence of the dlsease, at least ln some cases.
13
Blederman et al.
14
found a posltlve assoclatlon between
some psychosoclal adversltles (severe marltal confllct,
low socloeconomlc level, blg famlly, parental crlme,
maternal psychopathology and placement ln a foster
famlly) and ADHD.
The lnvestlgatlon lnto an assoclatlon between ADHD
and pregnancy or chlldblrth compllcatlons has ylelded
dlscrepant results, but tends to support the ldea that such
compllcatlons (toxemla, eclampsla, fetal post-maturlty,
length of dellvery, fetal stress, low blrthwelght, antepartum
hemorrhage, poor maternal health) may predlspose to the
dlsorder.
13
Recently, Mlck et al.
15
have observed a
slgnlflcant assoclatlon between exposure to tobacco and
alcohol durlng pregnancy and the presence of ADHD ln
chlldren even after control for famlly psychopathology
(lncludlng ADHD), soclal adversltles and comorbldlty wlth
conduct dlsorder. Other factors, such as perlnatal braln
lnjury to the frontal lobe may affect attentlon, motlvatlon
and plannlng, belng lndlrectly assoclated wlth the dlsease.
16
Most of the studles on posslble envlronmental agents only
revealed an assoclatlon of these factors wlth ADHD, but no
clear relatlon between cause and effect could be
establlshed.
13
Genetic factors
A substantlal genetlc contrlbutlon ln ADHD ls suggested
by classlc genetlc studles. Varlous famlly studles have
been conducted about ADHD, havlng conslstently shown
a slgnlflcant famlllal recurrence of thls dlsorder. The rlsk
for ADHD seems to be two tlmes to elght tlmes greater ln
parents of affected chlldren than ln the general populatlon.
13
All the evldence obtalned from famlly studles does not
rule out the posslblllty that famlllal transmlsslon of ADHD
has an envlronmental etlology. In thls regard, studles wlth
twlns and adopted chlldren are cruclal to determlne
whether a characterlstlc ls actually lnfluenced by genetlc
factors. The concordance between twln palrs ls nothlng
more than a measure of lnherltablllty, whlch represents an
estlmate of whlch portlon of the phenotype ls lnfluenced
by genetlc factors.
11
Most of these studles found
conslderable concordance for thls pathology, whlch was
slgnlflcantly hlgher between monozygotlc twlns than
between dlzygotlc ones. The estlmated lnherltablllty ls
hlgh, exceedlng 0.70 ln several studles, whlch suggests a
strong genetlc lnfluence.
11
Strlklng evldence of ADHD lnherltablllty ls provlded by
studles wlth adopted chlldren, slnce they can dlstlngulsh
between genetlc and envlronmental effects more efflclently.
Inltlal studles wlth adopted chlldren found a slgnlflcantly
hlgher frequency of ADHD among blologlcal parents of
affected chlldren than among foster parents.
11
A prevalence
of ADHD of approxlmately three tlmes among blologlcal
parents compared wlth foster parents also has been
observed recently.
17
A hlgher prevalence of ADHD among
blologlcal parents than among foster parents of probands
conflrms the contrlbutlon of lmportant genetlc factors to
the etlology of thls dlsorder.
There has been an lncreased lnterest ln molecular
genetlc studles about ADHD ln the last few years. The
major alm of these studles ls the genes that encode
components of the dopamlnerglc, noradrenerglc and
serotonlnerglc systems, slnce results obtalned from
neuroblologlcal studles strongly suggest the lnvolvement
of these neurotransmltters ln the pathophyslology of
ADHD.
18
Most molecular studles on ADHD have focused on the
dopamlnerglc system. Dopamlne transporter gene (DAT1)
was the lnltlal candldate for these studles, as the transporter
proteln ls lnhlblted by stlmulants used ln the treatment of
ADHD.
19
The flrst report on the assoclatlon of DAT1 wlth
ADHD was made by Cook et al.
20
These authors lnvestlgated
a varlable number of tandem repeats (VNTR) polymorphlsm
located ln reglon 3 of the gene. An assoclatlon was
detected wlth the allele of 480 bp (base palrs), whlch
corresponds to 10 coples of a 40-bp repeat (10R), uslng
haplotype relatlve rlsk (HRR). Later on, several studles
attempted to repllcate thls assoclatlon. Although some
negatlve reports exlst, most studles managed to detect an
effect of DAT1 on ADHD. The estlmated effect for DAT1 ls
qulte small, wlth an odds ratlo between 1.6 and 2.8.
21
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004 S63
Another gene ln the dopamlnerglc system that ls
wldely lnvestlgated ls the dopamlne 4 receptor gene
(DRD4). The great lnterest ln thls gene has resulted from
lts assoclatlon wlth a novelty seeklng personallty dlmenslon,
probably related to ADHD.
22
In addltlon, the product of
thls gene ls located ln braln reglons whose functlons are
lmpalred by the dlsease.
23,24
The maln polymorphlsm
lnvestlgated ln DRD4 ls a 48-bp VNTR, located ln exon 3,
reglon that supposedly encodes an lmportant functlonal
domaln of thls proteln.
12
LaHoste et al.
25
were the flrst to
detect the assoclatlon of thls gene wlth ADHD. The allele
wlth seven coples of the 48-bp repeat (7R), the same
related to the novelty seeklng personallty dlmenslon, was
suggested as rlsk allele. Although many subsequent studles
have reproduced the assoclatlon wlth DRD4, thelr results
are controverslal. A recent meta-analysls
26
suggested a
comblned odds ratlo of 1.4 for famlly studles and of 1.9 for
studles that used populatlon-based controls.
Vlrtually all the other genes ln the dopamlnerglc
system have been lnvestlgated for assoclatlon wlth ADHD,
lncludlng genes that encode D2, D3 and D5 receptors, and
enzyme genes related to dopamlne metabollsm.
12
Of
these genes, the most promlslng seems to be the dopamlne
5 receptor gene (DRD5). Lowe et al.
27
carrled out a jolnt
analysls of samples from 12 research centers, showlng a
small but slgnlflcant effect (odds ratlo = 1.24; p < 0.001)
for DRD5 gene on comblned ADHD wlth predomlnance of
attentlon deflclt. However, the number of lnvestlgatlons
for most of these markers ls stlll small and therefore does
not allow deflnltlve concluslons.
Few molecular studles have been conducted so far wlth
genes from the noradrenerglc system. These studles
focused malnly on the gene that encodes the dopamlne-
beta-hydroxylase (DH) enzyme, or DH locus, of whlch
a TaqI restrlctlon slte located ln lntron 5 ls the object of
lnvestlgatlon.
12
Although the functlonal meanlng of TaqI
restrlctlon slte on DH, and of DH on ADHD are not known
yet, the report of an assoclatlon ln two lndependent
samples suggests contrlbutlon of DH gene to the
susceptlblllty to thls dlsorder.
28
Genes of some adrenerglc
receptors also were lnvestlgated ln ADHD. Assoclatlons of
genes that encode 2A (ADRA2A) and 2C (ADRA2C)
receptors wlth hlgh scores of ADHD have been suggested
ln the llterature.
29
Addltlonal lnvestlgatlons lnto these
genes are necessary to conflrm or not thelr lnfluence on
the etlology of ADHD.
Recently, a posslble lnfluence of the serotonlnerglc
system on the etlology of ADHD has been lnvestlgated.
Posltlve results ln patlents wlth thls dlsorder were obtalned
for serotonln receptor 2A genes (HTR2A)
30
and serotonln
transporter,
31,32
whereas no assoclatlon was found for
the gene that encodes tryptophan hydroxylase (TPH),
whlch regulates serotonln synthesls.
33
Effects of the
lnteractlon between 5-HTT and DRD4 genes on sustalned
attentlon ln one-year-olds,
34
and on the response to
methylphenldate
35
were observed ln other studles. All
these flndlngs, albelt prellmlnary, lndlcate that the analysls
of these and other genes ln the serotonlnerglc system ln
dlfferent groups of ADHD patlents may result ln an
lmportant etlologlcal contrlbutlon.
Thus, the study of the etlology of ADHD ls stlll ln lts
lnfancy. Even wlth regard to genetlcs, whlch has been
extenslvely lnvestlgated, the results are contradlctory.
None of the lnvestlgated genes, not even DRD4 or DAT1,
may be consldered necessary or sufflclent to the
development of thls dlsorder. Thls ls greatly due to a
unlque etlologlcal heterogenelty, represented by the hlgh
cllnlcal complexlty of the dlsease. In the future, the study
of the etlology of ADHD wlll certalnly lnclude the
determl natl on of possl bl e "subphenotypes or
"endophenotypes, ln whlch thls heterogenelty ls low.
18
Neurobiology
The data on the neuroblologlcal substrate of ADHD are
derlved from neuropsychologlcal, neurolmaglng and
neurotransmltter studles. Although there seems to be an
agreement that no abnormal flndlng ln a slngle system of
neurotransmltters may be held responslble for a syndrome
as heterogeneous as ADHD, studles malnly lndlcate the
lnvolvement of catecholamlnes, especlally dopamlne and
noreplnephrlne. A detalled revlew on thls lssue can be
found ln Rohde & Rlesgo.
36
It ls common knowledge that the process of braln
maturatlon has a posteroanterlor progresslon, that ls,
flrst there ls the myellnatlon of the vlsual pathway,
whose developmental maturatlon wlndow opens near
the tlme of blrth and closes at around the second year
of llfe. Flnally, myellnatlon of anterlor areas takes place.
Therefore, from a neuronal developmental standpolnt,
a certaln level of pure hyperactlvlty ls acceptable ln
chlldren wlth no lnjury, up to approxlmately the fourth
and flfth years of llfe, as the prefrontal reglon only
completes lts myellnatlon at thls age.
37
A recent structural neurolmaglng study has revealed
that the evolutlonal path of the braln regardlng the
lncrease ln lntracerebral volumes ln ADHD chlldren follows
a parallel course wlth those who do not have the dlsease,
but always wlth slgnlflcantly smaller volumes, whlch
suggests that the events that trlggered the symptoms
(genetlc or envlronmental lnfluences) occurred early on
and were non-progresslve. The dlfferences between cases
and controls dld not seem to be related to the use of
psychostlmulants.
38
One of the flrst anatomlcal and functlonal theorles that
attempted to explaln the neuroblology of ADHD descrlbed
dysfunctlons ln the frontal areas and ln the subcortlcal
connectlons to the llmblc system. Therefore, at the
beglnnlng, there was only one attentlonal system, and
ADHD was regarded as a frontal lnhlbltory control over
llmblc structures. However, the theory of a slngle attentlon
center - albelt extenslvely conflrmed by neuropsychologlcal,
functlonal neurolmaglng, and neurotransmltter studles -
may explaln some but not all cases of ADHD. From an
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
S64 Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004
anatomlcal and functlonal polnt of vlew, there should be a
neural clrcultry wlth two attentlon systems: an anterlor
one, whlch seems to be dopamlnerglc and lnvolves the
prefrontal reglon and lts subcortlcal connectlons
(responslble for lnhlbltory control and executlve functlons
such as worklng memory), and a posterlor one, prlmarlly
noradrenerglc (responslble for the regulatlon of selectlve
attentlon).
36
The locus ceruleus also plays a vltal role ln
attentlon and ls baslcally comprlsed of adrenerglc neurons
only, becomlng very actlve ln response to speclflc stlmull.
39
Desplte the lmportance of the functlons ln both attentlon
systems for the neuroblology of ADHD, dlrect lmpllcatlons
of thelr reclprocal relatlons to thls dlsorder are stlll scarce.
Levy & Farrow
40
revlewed the prefronto-parletal network,
whlch llnks the anterlor attentlon system to the posterlor
attentlon system and ls the anatomlcal and functlonal
support for the worklng memory.
Diagnosis
Clinical picture
The classlc trlad of symptoms that characterlze thls
syndrome are lnattentlon, hyperactlvlty and lmpulslvlty.
Regardless of the classlflcatlon system, chlldren wlth
ADHD are easlly ldentlfled ln cllnlcs, schools and at home.
The descrlptlon of the trlad of symptoms ls shown ln Table
1 (DSM-IV dlagnostlc crlterla).
It should be underscored that lnattentlon, hyperactlvlty
and lmpulslvlty as lsolated symptoms may result from
many problems related to relatlonshlps (wlth parents and/
or colleagues and frlends), lnapproprlate educatlonal
systems, or may even be assoclated wlth other dlsorders
that are commonly observed ln chlldhood and adolescence.
Therefore, for the dlagnosls of ADHD lt ls always necessary
to contextuallze the symptoms ln the chllds hlstory. Some
clues that lndlcate the presence of ADHD are: a) length of
symptoms of lnattentlon and/or hyperactlvlty/lmpulslvlty.
Qulte often, chlldren wlth ADHD have a hlstory of symptoms
that start ln preschool age, or at least a perlod of several
months wlth lntense symptoms; b) frequency and lntenslty
of symptoms. For the dlagnosls of ADHD, lt ls cruclal that
at least slx symptoms of lnattentlon and/or slx symptoms
of hyperactlvlty/lmpulslvlty descrlbed above be frequently
present (each of the symptoms); c) perslstence of
symptoms ln several places and over tlme. Symptoms of
lnattentlon and/or hyperactlvlty/lmpulslvlty have to occur
ln dlfferent envlronments (e.g.: at school and at home)
and be constant durlng the study perlod. Symptoms that
occur only at home or only at school should warn cllnlclans
of the posslblllty that lnattentlon, hyperactlvlty or
lmpulslvlty may slmply reflect a chaotlc famlly sltuatlon or
an lnapproprlate educatlonal system. Llkewlse, osclllatlng
symptoms wlth asymptomatlc perlods are not characterlstlc
of ADHD; d) cllnlcally slgnlflcant consequences on the
chllds dally actlvltles. Symptoms of hyperactlvlty or
lmpulslvlty wlth no effect on chllds dally actlvltles may
reflect dlfferent functlonlng or temperament styles other
than a psychlatrlc dlsorder; e) understandlng the meanlng
of the symptom. For the dlagnosls of ADHD, lt ls necessary
that a careful assessment of each symptom, and not only
a llst of symptoms, be made. For lnstance, a chlld may
show dlfflculty followlng lnstructlons due to an opposltlonal
deflant behavlor towards parents or teachers, whlch
characterlzes a symptom of an opposltlonal deflant dlsorder
lnstead of ADHD. It ls essentlal to check whether the chlld
does not follow lnstructlons because he/she cannot
concentrate whlle they are belng glven. In other words, lt
ls necessary to check whether the supposedly present
symptom ls correlated wlth the baslc characterlstlcs of the
dlsease, that ls, attentlon deflclt and/or dlfflculty ln lnhlbltory
control.
3
Cllnlcal presentatlon may vary accordlng to the stage
of development. Symptoms related to hyperactlvlty/
lmpulslvlty are more frequent ln preschool chlldren wlth
ADHD than symptoms of lnattentlon. As more lntense
actlvlty ls characterlstlc of preschool chlldren, the dlagnosls
of ADHD should be made wlth cautlon before the age of slx
years. Thls, among other reasons, ls why lnformatlon on
a chllds normal development ls essentlal for the
psychopathologlcal assessment ln thls age group. The
llterature lndlcates that symptoms of hyperactlvlty subslde
ln adolescence, but symptoms of lnattentlon and lmpulslvlty
are more lntense ln thls perlod.
41
Diagnostic criteria
The dlagnosls of ADHD ls baslcally cllnlcal, based upon
clear and well-deflned operatlonal cllnlcal crlterla,
establlshed by classlflcatlon systems such as the DSM-IV
(Table 1), or ICD-10. By conductlng a study ln our settlng,
Rohde et al.
7
found lndlcatlve slgns of the adequacy of
DSM-IV crlterla, relnforclng thelr appllcablllty ln our settlng.
The DSM-IV proposes that at least slx symptoms of
lnattentlon and/or slx symptoms of hyperactlvlty/
lmpulslvlty are necessary for the dlagnosls of ADHD.
However, lt has been suggested that thls number could be
lowered ln adolescents and adults, slnce these lndlvlduals
may contlnue to show some slgnlflcant deflclt ln thelr
global development, even wlth less than slx symptoms of
lnattentlon and/or hyperactlvlty/lmpulslvlty. Thus, the
number of symptoms for the dlagnosls of adolescents ls
not so lmportant as the lmpalrment caused by these
symptoms. The level of lmpalrment should always be
assessed based on the adolescents potentlalltles and on
the amount of effort necessary to malntaln adjustment.
3
The DSM-IV and ICD-10 lnclude a crlterlon for the
age of onset of symptoms causlng lmpalrment (before
the age of seven years). However, thls crlterlon derlves
only from the oplnlon lssued by the commlttees ADHD
experts, wlthout any sclentlflc evldence that supports
lts cllnlcal valldlty.
42
It ls recommendable that cllnlclans
do not rule out the posslblllty of dlagnosls ln patlents
who have symptoms causlng lmpalrment before the age
of seven years.
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004 S65
Types of ADHD
The DSM-IV subdlvldes ADHD lnto three types: a)
predomlnantly lnattentlve type; b) predomlnantly
hyperactlve-lmpulslve type; c) comblned type.
5
The
predomlnantly lnattentlve type ls more common ln females
and, together wlth the comblned type, seems to have a
hlgher lmpact on academlc performance. Chlldren wlth the
predomlnantly hyperactlve-lmpulslve type are more
aggresslve and lmpulslve than those wlth the other two
types of ADHD, and tend to be unpopular and hlghly
rejected by thelr peers. The comblned type causes more
lmpalrment to global functlonlng, comparatlvely to the
other two types.
3
Comorbidities
Studles show a hlgh prevalence of comorbldlty between
ADHD and dlsruptlve behavloral dlsorders (conduct dlsorder
and opposltlonal deflant dlsorder), whlch ranges from 30
to 50%. The comorbldlty rate also ls slgnlflcant ln the
followlng dlseases: a) depresslon (15 to 20%); b) anxlety
dlsorders (around 25%); c) learnlng dlsabllltles (10 to
25%).
41,43
Several studles have shown a hlgh prevalence of
comorbldlty between ADHD and drug abuse or dependency
ln adolescence, especlally ln adulthood (9 to 40%). It ls
argued whether ADHD alone ls a rlsk factor for drug abuse
and dependency ln adolescence. The comorbldlty of ADHD
A. Either 1 or 2
(1) slx (or more) of the followlng symptoms of lnattentlon have perslsted for at least 6 months to a degree that ls maladaptlve and
lnconslstent wlth developmental level:
Inattention:
a) often falls to glve close attentlon to detalls or makes careless mlstakes ln schoolwork, work, or other actlvltles
b) often has dlfflculty sustalnlng attentlon ln tasks or play actlvltles
c) often does not seem to llsten when spoken to dlrectly
d) often does not follow through on lnstructlons and falls to flnlsh schoolwork, chores, or dutles ln the workplace (not due to
opposltlonal behavlor or fallure to understand lnstructlons)
e) often has dlfflculty organlzlng tasks and actlvltles
f) often avolds, dlsllkes, or ls reluctant to engage ln tasks that requlre sustalned mental effort (such as schoolwork or homework)
g) often loses thlngs necessary for tasks or actlvltles (e.g., toys, school asslgnments, penclls, books, or tools)
h) ls often easlly dlstracted by extraneous stlmull l) ls often forgetful ln dally actlvltles (2) slx (or more) of the followlng symptoms
of hyperactlvlty-lmpulslvlty have perslsted for at least 6 months to a degree that ls maladaptlve and lnconslstent wlth
developmental level:
Hyperactivity:
a) often fldgets wlth hands or feet or squlrms ln seat
b) often leaves seat ln classroom or ln other sltuatlons ln whlch remalnlng seated ls expected
c) often runs about or cllmbs excesslvely ln sltuatlons ln whlch lt ls lnapproprlate (ln adolescents or adults, may be llmlted to subjectlve
feellngs of restlessness)
d) often has dlfflculty playlng or engaglng ln lelsure actlvltles quletly
e) ls often "on the go or often acts as lf "drlven by a motor
f) often talks excesslvely
Impulsivity:
g) often blurts out answers before questlons have been completed
h) often has dlfflculty awaltlng turn
l) often lnterrupts or lntrudes on others (e.g., butts lnto conversatlons or games)
B. Some hyperactlve-lmpulslve or lnattentlve symptoms that caused lmpalrment were present before 7 years of age.
C. Some lmpalrment from the symptoms ls present ln 2 or more settlngs (e.g., at school [or work] or at home).
D. There must be clear evldence of cllnlcally slgnlflcant lmpalrment ln soclal, academlc, or occupatlonal functlonlng.
E. The symptoms do not occur excluslvely durlng the course of a pervaslve developmental dlsorder, schlzophrenla, or other psychotlc
dlsorder and are not better accounted for by another mental dlsorder (e.g., mood dlsorder, anxlety dlsorder, dlssoclatlve dlsorder,
or personallty dlsorder).
Table 1 - DSM-IV dlagnostlc crlterla for ADHD
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
S66 Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004
and conduct dlsorder ls recognlzably frequent, and conduct
dlsorder ls clearly assoclated wlth drug abuse/dependency.
Therefore, drug abuse/dependency posslbly occurs more
frequently ln a subgroup of adolescents wlth ADHD who
also present wlth conduct dlsorder. In other words, the
rlsk factor ls not ADHD per se, but the comorbldlty wlth
conduct dlsorder. Thls lssue therefore requlres further
lnvestlgatlon.
3
Procedures for diagnostic evaluation at the
pediatrician's office
Pedlatrlclans are the health professlonals who follow
patlents longltudlnally and can ldentlfy the slgns and
symptoms that mlght be suggestlve of ADHD at an earller
stage. Several studles have demonstrated that the
prevalence of ADHD at a pedlatrlclans offlce ls slmllar to
that found at a psychlatrlsts offlce.
44
The basls for dlagnosls conslsts of patlents hlstory,
observatlon of the patlents current behavlor and the
account of parents and teachers about the chllds
functlonlng ln the places he/she frequents. Wlth regard
to the source of lnformatlon, there ls poor agreement
between lnformers (chlldren, parents, and teachers)
about the chllds mental health. Chlldren often do not
lnform about behavloral symptoms and have low test-
retest concordance for ADHD symptoms. Parents seem
to be good lnformers for the dlagnostlc crlterla. Teachers
tend to provlde too much lnformatlon about ADHD
symptoms, especlally when another dlsruptlve behavloral
dlsorder ls concomltantly present. Wlth adolescents, the
usefulness of the lnformatlon glven by teachers
slgnlflcantly decreases, as adolescents have several
teachers (one for each subject) and each teacher spends
too llttle tlme wlth each class, whlch prevents them from
knowlng each student well enough. As observed, the
process of dlagnostlc evaluatlon necessarlly lnvolves
collectlon of data from the parents, chlldren, and
teachers.
3
Past cllnlcal hlstory of behavlor ls essentlal for dlagnostlc
deflnltlon, slnce only a small number of patlents present
the characterlstlc slgns and symptoms of ADHD durlng
assessment. One should recall that the absence of
symptoms at the pedlatrlclans offlce does not rule out the
dlagnosls. These chlldren often are able to control the
symptoms voluntarlly, or durlng actlvltles ln whlch they
are greatly lnterested. Therefore, many tlmes, they can
spend hours ln front of the computer or vldeogame, but
cannot spend a few mlnutes ln front of a book ln the
classroom or at home.
3
Lack of concentratlon and/or hyperactlvlty at school
ls one of the most frequent complalnts at the pedlatrlclans
offlce; whlch suggests more of a speclflc learnlng dlfflculty
than an attentlon deflclt. A detalled soclal and famlly
hlstory ls of paramount lmportance.
45
Pedlatrlclans
should pay attentlon to perlnatal hlstory, slnce varlous
studles show a hlgher prevalence of ADHD ln preterm
bables and low blrthwelght lnfants. Careful follow-up of
thls rlsk group ls lmportant for the early ldentlflcatlon of
slgns and symptoms that may lndlcate a posslble
dlagnosls of ADHD.
46
The "classlc hlstory of ADHD ls shown ln Table 2.
Table 2 - "Classlc hlstory of ADHD
Infant "Dlfflcult lnfant, greedy, annoyed, dlfflcult
to comfort, greater prevalence of cramps,
dlfflcultles to eat and sleep.
Preschool child More actlve than usual, adjustment
dlfflcultles, stubborn, annoyed and
extremely dlfflcult to satlsfy.
Schoolaged child Unable to focus, lnattentlon, lmpulslve,
lnconslstent performance, presence or
absence of hyperactlvlty.
Adolescent Restless, lnconslstent performance, unable
to focus, memory dlfflcultles at school,
medlcatlon abuse, accldents.
In cllnlcal pedlatrlc practlce, only the general lmpresslon
about the patlent ls not enough for establlshlng or rullng
out the dlagnosls. Short consultatlon tlme comblned wlth
other acute cllnlcal symptoms may hamper a more accurate
evaluatlon. It ls recommended that whenever some
behavlor that mlght lnterfere wlth patlents functlonlng at
school or at home ls notlced, the pedlatrlclan should focus
on the assessment of patlents development.
Besldes cllnlcal hlstory, the use of scales for slgns or
symptoms of ADHD and behavloral dlsorders ls wldely
accepted, although pedlatrlclans do not employ them on
a routlne basls. An lnstrument deslgned for the observatlon
of behavlor by teachers (e.g.: Conners teachlng ratlng
scale)
47
may be qulte useful ln data collectlon. Levlne
48
devlsed a set of questlonnalres to be used by pedlatrlclans,
whlch lncludes questlons about attentlon and behavlor,
wlth the alm of systematlzlng data collectlon and offerlng
a detalled proflle of the chllds attentlon characterlstlcs.
Pedlatrlclans should not lose track of chllds development,
whlch goes beyond thelr blologlcal vulnerablllty to ADHD.
Chllds lnteractlon wlth the envlronment and hls/her famlly
may eventually contrlbute to dlagnosls, ln addltlon to
determlnlng the quallty and success of lnterventlons.
49
Stlll regardlng addltlonal evaluatlon, hearlng and
vlsual assessment are fundamental, as deflclts ln sensory
functlons may result ln lmportant attentlon and
hyperactlvlty problems. Neurologlcal screenlng ls
relevant for the excluslon of braln dlsorders that mlght
mlmlc ADHD and often ls valuable to relnforce the
dl agnosl s. The data obtal ned from evol utl onal
neurologlcal screenlng are lmportant.
50
As far as
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004 S67
psychologlcal testlng ls concerned, Wechsler Intelllgence
Scale for Chlldren
51
allows for a cognltlve evaluatlon of
the chlld, belng useful ln dlfferentlal dlagnosls between
mental retardatlon and ADHD. Other prevalent dlsorders
such as the fraglle X syndrome also have to be ruled out,
as thls dlsorder may cause attentlon deflclt, hyperactlvlty
and lmpulslvlty. Other neuropsychologlcal tests (e.g.:
Wlsconsln card-sortlng test, contlnuous performance
test - CPT or Stroop test), as well as neurolmaglng
exams (CT scan, magnetlc resonance, or cranlal SPECT)
are stlll part of the research and not of cllnlcal
asssesment.
41,52
Outcome
Formerly, chlldren wlth ADHD were belleved to
overcome thelr symptoms when they reached puberty.
However, recent prospectlve studles that followed up
chlldren wlth ADHD show perslstence of the dlagnosls ln
up to 70-80% of cases ln lnltlal to lntermedlate
adolescence.
53,54
Conservatlve estlmates state that
approxlmately 50% of adults dlagnosed as havlng ADHD
ln chlldhood contlnue to have slgnlflcant symptoms
assoclated wlth functlonal lmpalrment. Hyperactlvlty
decreases durlng development, but attentlon deflclts
and lmpulslvlty, especlally cognltlve lmpulslvlty (actlng
before thlnklng)
54
stlll perslst.
Throughout development, ADHD ls assoclated wlth an
lncreased rlsk of low school performance, repeatlng a
year, expulslon and suspenslon from school, dlfflcult
relatlonshlps wlth famlly and frlends, development of
anxlety, depresslon, low self-esteem, conduct dlsorders
and dellnquency, early experlmentatlon wlth and abuse of
drugs, car accldents and speed tlckets, as well as dlfflculty
establlshlng relatlonshlps ln adulthood, ln marrlage and at
work.
24
Nevertheless, as already mentloned, part of thls
outcome may be assoclated wlth the comorbldlty wlth
conduct dlsorder and not only wlth ADHD.
Treatment
Treatment of ADHD conslsts of a multlple approach,
lncludlng psychosoclal and psychopharmacologlcal
lnterventlons. Recently, the subcommlttee on ADHD of the
Amerlcan Academy of Pedlatrlcs has publlshed guldellnes
for cllnlcal pedlatrlclans on the treatment of ADHD.
55
These guldellnes conslst of flve baslc prlnclples:
1) Pedlatrlclans should establlsh a treatment program
that acknowledges ADHD as a chronlc dlsease;
2) Pedlatrlclans, along wlth parents, chlldren and teachers,
should speclfy the alms regardlng treatment outcome;
3) Pedlatrlclans should recommend the use of stlmulants
and/or behavloral therapy, lf approprlate, to mlnlmlze
target symptoms ln chlldren wlth ADHD;
4) When the selected management does not meet the
establlshed goals, pedlatrlclans should reassess the
orlglnal dlagnosls, and check whether all approprlate
treatments were used, treatment adherence, and the
presence of comorbldltles;
5) Pedlatrlclans should systematlcally glve chlldren wlth
ADHD a feedback, monltorlng the establlshed goals
and adverse events through the lnformatlon obtalned
from the chlldren themselves, famlly and school.
Wlth regard to psychosoclal lnterventlons, lt ls
fundamental that pedlatrlclans educate the famlly about
the dlsorder, glvlng them clear and accurate lnformatlon.
An example of lnformatlve llterature for famllles can be
found ln Rohde & Benczlck.
56
Many tlmes, parents have to
go through a tralnlng program on behavloral lnterventlons,
so that they learn how to deal wlth thelr chlldrens
symptoms. It ls lmportant that parents know the best
strategles so as to help thelr chlldren organlze and plan
thelr actlvltles. For lnstance, these chlldren need a study
envlronment that ls qulet, conslstent, and does not have
many vlsual stlmull. In addltlon, these programs should
offer tralnlng ln speclflc technlques ln glvlng commands,
strengthenlng the soclal adaptlve behavlor, and mlnlmlzlng
or ellmlnatlng maladapted behavlor (e.g.: through posltlve
relnforcement).
55
Interventlons at school also are lmportant. In thls
regard, teachers should ldeally be aware of the necesslty
of a well-structured classroom, wlth few students.
Conslstent dally routlnes and a predlctable school
envlronment help these chlldren to keep thelr emotlonal
control. Actlve teachlng strategles that comblne physlcal
actlvlty wlth the learnlng process are essentlal. Tasks
should not be too long and have to be explalned step by
step. It ls lmportant that students wlth ADHD have as
much personallzed attentlon as posslble. They should slt
ln the front row, close to the teacher and far from the
wlndow, that ls, ln a place where they have fewer chances
of gettlng sldetracked. Qulte often, chlldren wlth ADHD
need recap classes to go over some lessons. Thls occurs
because they already have learnlng gaps at dlagnosls, due
to ADHD. Sometl mes, these chl l dren need
psychopedagoglcal counsellng that ls focused on thelr
learnlng style, for lnstance, aspects regardlng the
organlzatlon, tlmlng and plannlng of actlvltles. Psychomotor
re-educatlon ls lndlcated for lmproved control of
movements.
3,41
In psychosoclal lnterventlons focused on chlldren and
adolescents, cognltlve-behavloral therapy ls the most
wldely studled modallty, wlth sclentlflcally proven efflcacy
ln the treatment of central symptoms (lnattentlon,
hyperactlvlty, lmpulslvlty), and assoclated behavloral
symptoms (opposltlon, deflance, stubbornness), especlally
behavloral treatments (see Knapp et al.
57
for a detalled
revlew on thls toplc). Among behavloral treatments,
parental tralnlng seems to be the most efflclent modallty.
However, recent results of the MTA study (multlcenter and
well-deslgned cllnlcal trlal that followed up 579 chlldren
wlth ADHD for 14 months, dlvlded lnto four groups: drug
therapy, behavloral psychotherapy wlth chlldren and
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
S68 Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004
guldance for parents and teachers, comblned approach,
and communlty-based treatment) clearly showed a hlgher
efflclency of drug therapy ln the treatment of central
symptoms compared to psychotherapy and the communlty-
based approach. The comblned approach (drug therapy +
behavloral psychotherapy wlth chlldren and guldance for
parents and teachers) dld not demonstrate hlgher efflclency
ln treatlng central symptoms comparatlvely to drug
therapy.
58
A more careful lnterpretatlon of results suggests
that proper drug therapy ls essentlal to the management
of ADHD.
Wlth regard to psychopharmacologlcal lnterventlons,
the llterature clearly lndlcates stlmulants as flrst-llne
treatment for ADHD.
59
There are over 150 methodologlcally
sound controlled studles showlng the efflcacy of these
drugs.
60
In Brazll, methylphenldate ls the only commerclally
avallable stlmulant. Therapeutlc dose ranges from 20 to
60 mg/day. As methylphenldate has a short half-llfe (3 to
4 hours), lt may be admlnlstered three tlmes a day; one
ln the mornlng, another one at mldday, and the last one
ln the evenlng. Thls ls especlally lmportant ln those
patlents wlth tasks that requlre attentlon at the end of the
day. Some patlents do not tolerate the thlrd dose, and
have remarkable lnsomnla as a result. These patlents
should recelve the medlcatlon twlce a day. In some of
these cases, comblnatlon wlth clonldlne may brlng some
beneflts.
61
Two formulatlons wlth a long-lastlng effect and
glven ln a slngle dose wlll soon be avallable ln Brazll. One
of them releases two "pulses, mlmlcklng the admlnlstratlon
of short-actlng methylphenldate twlce a day. The other
formulatlon conslsts of long-actlng methylphenldate (OROS
system), whose effect lasts for up 12 hours. The lnnovatlve
capsule technology allows constant release of the drug,
avoldlng varlatlons ln serum concentratlons. Around 70%
of ADHD patlents have an approprlate response to and
good tolerance of stlmulants, wlth reductlon of at least
50% of baslc symptoms.
60
The most common adverse
effects assoclated wlth the use of stlmulants are: loss of
appetl te, l nsomnl a, l rrl tabl l l ty, headache, and
gastrolntestlnal dlstress.
60
Controversles over the use of
methylphenldate lnclude: a) lnterference wlth growth -
recent studles have shown that the use of methylphenldate
does not slgnlflcantly change growth. Adolescents wlth
ADHD treated or not wlth methylphenldate reach late
adolescence wlth slmllar helght;
62
b) potentlal abuse of
methylphenldate - a recent meta-analysls clearly shows a
slgnlflcantly hlgher prevalence of abuslve use/drug
dependency ln adolescents wlth ADHD who were not
treated wlth stlmulants compared to those who recelved
stlmulants.
63
However, several studles have suggested
the posslblllty of lnapproprlate use of stlmulants by
persons who do not suffer from ADHD; c) length of
treatment - lndlcatlons for medlcatlon-free perlods, or for
medlcatlon dlscontlnuatlon durlng vacatlons from school
are controverslal. The dlscontlnuatlon of methylphenldate
use on weekends may be lndlcated for those chlldren ln
whom symptoms are more detrlmental to school
performance, or for those adolescents ln whom the control
over the use of alcohol or llllclt drugs ls dlfflcult on
weekends.
64
Dlscontlnuatlon ls lndlcated when the patlent
remalns asymptomatlc for about one year, or when
symptoms lmprove substantlally. Medlcatlon ls dlscontlnued
ln order to assess whether lt ls necessary to malntaln the
drug therapy.
Over 25 studles show the efflcacy of trlcycllc
antldepressants ln the treatment of ADHD. Once agaln,
most studles lnclude school-aged chlldren.
60
Cllnlcally,
trlcycllc antldepressants are lndlcated ln cases ln whlch
there ls no response to stlmulants and ln the presence of
comorbldlty wlth tlc dlsorders or enuresls. The followlng
aspects related to the use of trlcycllc antldepressants
should be underscored: a) dose - the approprlate dose of
lmlpramlne ranges from 2 to 5 mg/kg/day. Underdoses of
trlcycllc antldepressants for the treatment of chlldren ls a
common practlce ln our settlng; b) cardlotoxlc effects -
the lnternatlonal llterature descrlbes some cases of sudden
death ln chlldren recelvlng deslpramlne. Very llkely, these
deaths are not dlrectly related to the use of the medlcatlon.
However, to be on the safe slde, any chlld recelvlng
trlcycllc antldepressants should be electrocardlographlcally
monltored before, durlng and after treatment.
65
Some studles also demonstrate the efflclency of other
trlcycllc antldepressants ln treatlng ADHD, especlally of
buproprlon. The dose of buproprlon ranges from 1.5 to 6
mg/kg/day, glven ln two or three doses; doses above 450
mg/day remarkably lncrease the rlsk of selzures, whlch
are the maln restrlctlon on lts use. Major slde effects
lnclude agltatlon, dry mouth, lnsomnla, headache, nausea,
vomltlng, constlpatlon and tremors.
66
Recently, a meta-analysls on the use of clonldlne ln
ADHD found a posltlve effect on symptoms; the efflclency
of clonldlne can be compared to that of trlcycllc
antldepressants.
67
Its use ls lndlcated ln the presence of
comorbldltles for whlch the use of stlmulants ls
contralndlcated or when stlmulants are not tolerated.
Doses range from 0.03 to 0.05 mg/kg/day and the major
contralndlcatlon ls preexlstence of cardlac conductlon
dlseases, due to lts slde effects on the cardlovascular
system .
61
Nevertheless, lt has been cllnlcally comblned
wlth stlmulants, especlally ln cases ln whlch the lndlvldual
use of stlmulants causes sleep dlsorders or symptom
recurrence at the end of the day.
Atomoxetlne, recently approved by FDA, ls a new
pharmacologlcal optlon for the treatment of ADHD, and
should be avallable ln Brazll very shortly. Atomoxetlne ls
a non-stlmulant drug and a selectlve noreplnephrlne
reuptake lnhlbltor, wlth low afflnlty for other receptors and
neurotransmltters. It reaches lts peak serum concentratlon
wlthln 1 to 2 hours wlth a half-llfe around flve hours. The
average dose ls of 1.4 mg/kg/day. Cllnlcal trlals lndlcate
that lt ls efflclent even wlth a slngle dally dose. So far,
atomoxetlne has been lnvestlgated ln approxlmately 2,500
chlldren and adolescents wlth ADHD ln open-label and
Attentlon deflclt/hyperactlvlty dlsorder - Rohde LA & Halpern R
Jornal de Pedlatrla - Vol. 80, No.2(Suppl), 2004 S69
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Correspondlng author:
Luls Augusto Rohde
Servlo de Pslqulatrla da Infncla e Adolescncla
Hospltal de Clnlcas de Porto Alegre - 4
o
andar
Rua Ramlro Barcelos, 2350
CEP 90035-003 - Porto Alegre, RS, Brazll
Tel./fax: +55 (51) 3321.3945
E-mall: lrohde@terra.com.br
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