Abstract
After a detailed clinical definition of ADHD and its diagnostic criteria, the author analyses the most accredited pathogenetic hypotheses. She points out the important role of child neuropsychiatrists, paediatricians and developmental psychologists in early diagnosis of the disorder and in setting up a therapeutic project with appropriate intervention strategies. Finally, in the light of neuropsychological functioning of an ADHD child, she underlines how the centrality and efficacy of the therapeutic project determines a multimodal treatment combining pharmacological treatment with psycho-educational interventions. Attention Deficit Hyperactivity Disorder is one of the most common psychiatric pathologies that becomes apparent in some children in the preschool and early school years and affects their performance in school, social relationships and behaviour at home. This complex unhealthy condition may appear with different clinical manifestations from the preschool years into adulthood and involves and impairs numerous areas of development and social functioning, predisposing them to a severe psychiatric pathology and/or social hardship in later life.
The characteristic symptoms of ADHD appear in various areas such as the cognitive (inattention), motor (hyperactivity) and behavioural/relational (impulsivity). This complex and diversified disorder confuses parents and teachers who wait in vain for the continually distracted and restless child they are unable to control to calm down and change with age. It took the scientific community a long time and many attempts to finally agree on the definition of the syndrome.
In the early 20th century impulsive, uninhibited and hyperactive children were defined as affected by hyperkinetic syndrome. In French literature, Wallon in his L'enfant turbolent (1925) introduced the notion of psychomotor instability, later developed by Ajuriaguerra.
Around the '60s the concept of disorder from "Minimal brain damage" was suggested in Anglo-Saxon literature. In the '70s in the USA it was first defined as "Attention Deficit Disorder" and later as "Attention Deficit Disorder with or without Hyperactivity" (1985).

 

This definition disregarded any consideration of possible organic causes and focused mainly on behavioural and social adaptation difficulties. These frequent changes in the definitions bear witness to the uncertainty researches have had in finding the causes of the disorder. In recent years, the syndrome was more accurately defined in the studies conducted in the USA and Europe by major scientific institutes such as the American Academy of Child Adolescent Psychiatry, the American Association of Paediatrics, the European Association of Child Adolescent Psychiatry and international health institutions such as NIMH and NICE. This allowed a clearer etiological and semiotic definition thus permitting diagnostic and therapeutic courses shared and defined by specific guidelines, also reconsidered and reformulated by SIMPIA in 2002. Today we know a great deal more about this very complex disorder. First and foremost, the score of symptoms can be traced back to neurobiological causes, but although the scientific community agrees in defining ADHD as a disorder characterised by core symptoms such as hyperactivity, impulsivity and attention/concentration deficit - not forgetting the diagnostic importance of disorganised everyday life and the correlated symptoms - there are widely different opinions in evaluating the gravity of the symptoms and in justifying the clinical importance of their manifold manifestations. ICD 10 (WHO 1927) and DSM IV (APA 1994) agree that the syndrome involves disorders pertaining to various areas: cognitive, motor and relational-behavioural.
The former having more restrictive criteria than the latter allows identifying only a small number of children, i.e. only the most serious cases; in fact, according to ICD 10 the symptoms of inattention, hyperactivity and at least one symptom of impulsivity must be present at the same time in the same child in more than one setting.
According to this classification, the incidence of the disorder known as Hyperkinetic Syndrome is estimated to be present in 1-1.5% of children in school age. ICD 10 tends to exclude multiple diagnosis and hence if both the ADHD diagnosis and the conduct disorder criteria are satisfied, the child is diagnosed with Hyperkinetic Disorder.
DSM IV, preferred by ADHD experts because it is more analytical and more focused on comorbidity, divides the disorder into three clinical types according to the pattern of behaviour: predominantly inattentive type (that does not show significant hyperactive/impulsive behaviour), predominantly hyperactive/impulsive type (that does not show significant inattention) or the combined type (that displays both inattentive and hyperactive/impulsive symptoms).
Two groups of symptoms are considered: a first group with 9 items pertaining to the attention deficit, a second group with 6 items pertaining to hyperactivity and 3 items of impulsivity (Tables 1 and 2).
When six or more symptoms pertaining to either of the two groups persist for at least six months, it is diagnosed as pathological.
The disorder must appear before the age of seven and must be present in two or more settings with clinically significant impairment of social and scholastic functioning. The symptoms worsen in settings where organised help is not provided, whereas they can be contained or not appear at all if the child receives individual care with stimulations that arouse his or her interest. Categorical diagnosis, according to the quantitative criteria suggested by DSM IV, cannot leave out a dimensional diagnosis that allows a qualitative assessment of the consequent cognitive and behavioural dysfunction.
The dimensional approach responds to all the diatribes on the existence of ADHD, because when the symptoms of inattention and hyperactivity/impulsivity - inappropriate for the child's age - affect his or her functioning, we can safely say that it is a disorder. Children who are inattentive or easily distracted find it difficult to pay attention to details and are unable to complete a task they have started.
These children appear distracted all the time, they avoid carrying out activities requiring attention to details or organisational skills, they often lose important objects and forget important tasks. Children who are impulsive - a characteristic that remains quite stable during development and also affects adults with ADHD - have trouble organising complex actions with a tendency to jump from one task to another, and they find it hard to wait to take their turn in games or group activities. This impulsivity is generally associated with hyperactivity. ICD 10 also includes among the symptoms possible uninhibited social relationships, acting rashly in dangerous situations, impulsively breaking the social rules.
All these symptoms are not caused by cognitive deficit but by the objective difficulties in self-control and planning skills. In the absence of an adult supervisor, these children quickly get tired, find it hard to control their impulses and to wait for gratification. Imprisoned in their disorder, children with ADHD are unable to use their cognitive potential, which affects their performance at school with negative attributions by the environment and a cognitively weak self-development.
When these patterns of behaviour are persistent in all settings and constitute the constant of the child, they may impair his or her planning and execution skills of complex executive function procedures.

 

 

The studies on the causes of ADHD have clarified the difference between factors that determine the onset of the disorder and those that determine its persistence. In current literature etiological neurobiological hypotheses relating to genetic and sometimes microinjury aspects are predominant and these are accompanied by environmental factors with triggering and amplifying effect on the clinical expressivity. In the last 10 years, some studies based on modern image processing techniques (RMC and PET) have shown which improperly functioning regions of the brain might explain the symptoms of ADHD. In a study conducted in 1996, Castellano and Rappaport demonstrated that the right prefrontal cortex, the two basal ganglia, the caudate nucleus and the globus pallidus are significantly less extensive in children affected by ADHD. The genetic hypothesis in the aetiology of the disorder is supported by numerous studies that confirm that the smaller brain structure is caused by a dysfunction of some of the numerous genes that are normally active during formation and development of the prefrontal cortex and the two basal ganglia. Most researchers are of the opinion that ADHD is a polygenic disorder. Studies on homozygotic twins seem to confirm this data and inheritability is estimated to be 80-90% (J.Gillis 92, University of Colorado; Gjone and Sudedet, University of Oslo; Stevenson, University of Southampton). Other studies show that a genetic influence exists in non-twin brothers and sisters of ADHD children, who are 5-7 times more likely to develop the disorder than children of unaffected families. There is a 50% probability that children of a parent affected by ADHD will experience the same difficulties. The genetic factors that have been connected with ADHD include premature birth, the mother smoking or drinking alcohol during pregnancy, exposure to heavy metals in early infancy and brain injury, especially involving the cerebral cortex. Contrary to popular belief, no correlation between ADHD, dietary factors and allergies has been demonstrated. The maintenance factors, on the other hand, depend on the structure of the environment, which in any case is of secondary importance considering the serious psycho-emotional consequences of the failures and frustrations in the relational, social and scholastic areas. The psychosocial factors do not constitute the primary cause of the disorder, but modulate the activation of the genetic predisposition. In families with ADHD children different patterns of parent-child relationships can be observed, none of these patterns is predominant and all of them can also be seen in families with normal children. Confrontational interactions and negative verbalizations appear to be more closely related to Oppositional Defiant Disorder and Conduct Disorder than to the core symptoms of ADHD. The attention disorder is secondary to a development defect in the circuits that lie at the base of inhibition and self-control. The reduced self-control negatively affects the other brain functions necessary to stay attentive and hence also the ability to wait for immediate reward in view of subsequent greater advantage. R. Berkely maintains that these children are 30% retarded in self-control and that 30% should therefore be deducted from their age in order to assess the real degree of the disorder and adjust the tasks to be carried out accordingly. In the last 10 years specific brain areas able to modulate attention have been identified. In particular, there are specific brain areas in the medial prefrontal cortex which allow choosing from different possible behaviours and mental activities in response to a stimulus. These areas are capable of coordinating a pattern of behaviour and an activity while inhibiting others. Any task is performed based on this capability of inhibiting some motor and emotional responses to external stimuli. To achieve an objective, be it in work or play, children need to remember the purpose (retrospection), define what is needed to achieve the objective, know how to repress their emotions, and be able to motivate themselves. An EEG of children with ADHD compared with controls without ADHD shows a slight reduction in electric activity. Also PET confirms reduced activity of the frontal regions in children with ADHD. The significance of this data is evident, since the fibres that connect these areas to the limbic system originate here, exercising a control function on the emotions, motivations and memory. This is why inattentive and hyperactive children find it hard to control their emotions, are poorly motivated, and do not use their memory skills to their full potential. Nuclear resonance has shown that children with ADHD do not have the physiological asymmetry of the frontal lobes; the right frontal lobe, caudate nucleus and globus pallidus are approximately 10% smaller in volume than in the controls. A slower activation time and less oxygen consumption was also found. Various functions of the cortex and the caudate nucleus are modulated by dopamine, noradrenaline and serotonin; it has recently been observed that there are frequent variants of genes that code via the dopamine carrier and the D4 dopamine receptor in children with ADHD. The first mutation makes the carriers excessively active with early elimination of the dopamine before it has had the chance of linking to the specific receptors situated in an adjacent neuron.

The second type of mutation can make the receptors less sensitive to dopamine. The lower level of dopamine in the frontal brain regions in ADHD children may normalise and give values superimposable on those recorded in the controls by administering methylphenylate that acts by slowing down recaptation of dopamine or amphetamine which increase the release. It should be remembered that the prefrontal areas, when they are intact, curb behaviour and hence control impulsivity, planning of actions and staying attentive for long periods of time. All this cannot occur when these areas are hypoactivated. We can therefore come to the same conclusion as Berkely that the genetic and structural defects in children with ADHD are responsible for the attention disorder associated with hyperactivity, reducing the capability of inhibiting inappropriate behaviour and self-control. It has been calculated that this disorder is prevalent in 3-4% of children in school age. Three studies conducted in Italy - one in Umbria and Tuscany by Gallucci and Coll. in 1993, two in Emilia by Camerini and Coll. in 1999 and by Marzocchi and Cornoldi in 2000 - on the general child population show a prevalence of about 4%, roughly similar to North American and North European estimates. It should be pointed out that the screening tools used for a first diagnostic orientation (DSM III-R and DSM IV ) overrate the problem, as they look at it within the wider spectrum of conduct disorder. In the extreme estimates, the prevalence would be reduced from 18% to 3.9% after dimensional evaluation with second-level diagnostic models. The incidence varies in relation to the urban-rural parameter and appears higher in lower socio-economic groups; there do not appear to be significant differences between the various ethnic groups. ADHD is to a significant extent associated with social adaptation disorders (antisocial personality, alcoholism, drug addiction, criminality), low academic and occupational adaptation and psychiatric problems, so much so that it is considered one of the best predictors in childhood for poor psychosocial adaptation in adulthood. Even though it seems that this is more a legacy of the comorbid rather than the simple forms and those with neuropsychological disorders and that it strictly depends on the setting in which the ADHD child grows up, it is the persistence of ADHD that represents the worst psychosocial prognosis factor, indicating that the longer the effects of the disorder last, the greater the impact on psychological growth and development. The inevitable failures the ADHD child will accumulate in his or her experiences in social, school and family life will inevitably encourage development of oppositional and defiant traits, which represent a very problematic aspect of ADHD. Given the complexity of ADHD, the core symptoms, the specific symptomatological profiles (aggressiveness, social dysfunction, immaturity, isolation) and the associated behavioural problems must always be distinguished. The main difficulties involve the self-control processes, inhibition of impulsive reactions and modulation of the levels of activation in relation to the environmental demands; in addition, the attention span, selective powers and short-term working memory are reduced. Because of their inattention these children show an apparently faster perceptive analysis, which in actual fact conceals superficiality and haste in performing tasks, planning difficulties, poor method and sequentiality in both thinking and practical tasks. Children with ADHD sometimes also manifest secondary symptoms on top of the primary ones that qualify the disorder itself. They are defined as secondary symptoms since they are the result of the interaction of the main characteristics with the social environment in which the child grows up. Biological measurements for ADHD not being available, the diagnosis is based on evaluation criteria for the behavioural symptoms and on a careful evaluation of the child conducted by a child neuropsychiatrist with experience of the disorder. In fact, the local developmental neuropsychiatric health services in agreement with the school and social services and family paediatricians should act as liaisons to help the family of a child with suspected ADHD deal with the disorder. Other figures in mental health in the years of growth are involved in the diagnosis and treatment of ADHD, such as psychologists and psychotherapists. Physicians must be extremely careful in conducting the diagnostic process and their assessment must involve not only the child but also his or her parents and teachers. Information must be gathered from multiple sources on the behaviour and functional impairment of the child, and the cultural and environmental factors in the child's life must always be considered. Finally, the core symptoms of the disorder must be distinguished and the associated psycho-behavioural symptomatological profiles. Although no specific diagnostic tests are available, including questionnaires and psychological tests (Table 3,4), the neuropsychiatric evaluation is very important for the development of an ADHD child, since an early diagnosis with consequent timely multimodal treatment is fundamental for a favourable prognosis and containment of comorbidity. The diagnosis is clinical and based on information from multiple sources and on observation of the child. Fundamental elements of the diagnosis are identifying false positives, i.e. differential diagnosis and comorbidity. The diagnostic protocol includes an in-depth clinical interview with the parents on all the sectors of life and history of the child which may throw light on the problem, and especially examining the history of the problems, that is, when they first appeared, how they progressed and how frequently they occur, since it is important to verify whether the symptoms are simply isolated episodes or enduring as in ADHD. It must be established whether the parents or family have shown symptoms of ADHD, examine the medical history of the mother - also relating to use of alcohol and cigarettes during pregnancy, which determine alteration of the dopamine receptor - the perinatal phase, any post partum complications, psychomotor and linguistic development stages, wake-sleep rhythms, any family problems, style and interaction of the parents. An interview with the child is useful from about 6-7 years of age to find out what he or she thinks about family functioning and the relationships with his/her peers in and out of school. The clinician must also understand the child's interpersonal style, the level of self-esteem, the relationship with his/her problem. But if all this allows making a more or less accurate suspect diagnosis, only behavioural assessment and objectivation of the pathognomonic symptoms through DSM IV allow confirming the suspicion or not. In the past, the poor knowledge of ADHD did not allow early and functional diagnosis of the disorder. To reduce the variability, it is opportune to resort to standardised instruments such as semistructural interviews. K-SADS is a semistructured interview to assess both present and past psychopathological episodes in children and adolescents according to the criteria of DSM III-R and DSM IV. For the quantitative definition of the gravity of the disorder, rating scales are used that can be applied to many diagnostic categories and to internalised symptoms (anxiety, depression, self-esteem) and externalised symptoms (ADHD, aggressiveness) and also to specific constructions such as cognitive style. They may be self-evaluation or hetero-evaluation scales and evaluate the extent of subjective or social impact (Conner's rating scale, Becker depression-BDI, Children depression rating scale-CDRS, Children depression-CDI, Young mania rating scales-YMRS, CBCL, CYBOCS, SNAIP IV, PARS, GAD). The use of rating scales in clinical trials to measure the "change" has increased in the last ten years. It is important not to make a diagnosis based only on the questionnaires; the rating scales completed by the parents, teachers and the child are valuable tools as diagnostic completion for quantitative evaluation to identify any associated pathologies, assess the clinical progress or the response to treatments. Clinical behavioural observation, contrary to the past, is very accurate and it is important to carry it out in different contexts because ADHD cannot be observed in highly structured or new settings, when the child is busy with interesting activities, when he or she is getting individual attention in a controlled and supervised setting, when rewards are frequently ladled out. On the contrary, the child worsens in unstructured situations, when having to do repetitive tasks, in boring situations, where there are many distractions, when there is minimum supervision, when sustained attention or a mental effort is required, during activities when they have to wait for their turn. First of all, the child's initial attitude when faced with a new situation needs to be observed: an ADHD child will typically have mood swings, desultory relationships, enthusiastically start a game but be unable to play it to the end. The overall medical assessment must include the recent and remote past medical history, including the family history. In the physical and neurological examination the child's height, weight, head circumference, arterial pressure, heart rate must be evaluated. An objective neurological examination must be carried out, any dimorphism sought, and the sensory, perceptive, motor and linguistic functions evaluated. If necessary, routine haematological tests, EEG, neuro images, genetic evaluations, metabolic examination and ECG should be performed. As far as the psychological assessment is concerned, neuropsychological tests should be conducted only where indicated, bearing in mind that no specific test for ADHD exists and remembering that an ADHD child's specific functioning is characterised by his or her great "variability". IQ needs to be tested and also reading, writing and mathematical skills, central neuro-psychological functions (attention, language learning, perceptions, memory, motor skills) and the five domains of the executive functions (planning, working memory, inhibition, verbal fluency, cognitive flexibility). Consistency between observation and clinical evaluation of the child, semistructured interviews, rating scales and neuropsychological evaluation would be desirable; the entire diagnostic process will be facilitated if carried out by a professional team specialised in ADHD.
A physician approaching this heterogeneous disorder - often associated with oppositional defiant disorder, conduct disorder, tic disorders, anxiety and dyslexia - must bear in mind that an extensive evaluation from the behavioural, cognitive, emotional and social functioning viewpoint requires skill, patience and time.
An accurate differential diagnosis and careful evaluation of the comorbidity will be necessary, which will allow the physician to determine clear qualitative forms with specific implications for the treatment. There are about 30% pure forms of ADHD against 70% of those with comorbidity. Approximately 25% of children with ADHD have anxiety and depression problems, prevalently in the forms without hyperactivity. The association with oppositional defiant disorder oscillates between 50% and 60%, and with conduct disorder around 30%. The earlier a conduct disorder appears, the greater the likelihood of development towards anti-social behaviour.
Therefore, ADHD must be recognised and treated early. Comorbidity is present also with disorders of the autistic spectrum and often diagnosis of the Asparger syndrome is preceded by a diagnosis of ADHD. Tic disorders overlap ADHD in about 20% of cases, they appear in school age and improve before the onset of ADHD (Table 5).
Comorbidity with sleeping and motor coordination problems affect 50% of cases.
They may also be accompanied by specific learning disorders: dyslexia, dyscalculia, bipolar disorder, mental retardation. Considering the complexity of ADHD and the course of the disorder in the various age groups, it is fundamental that once diagnosed the clinician prescribe multimodal treatment to help the family and the patient deal with the disorder and its psychopathological consequences, which in the most severe cases leads to emotional problems, an aggressive attitude, antisocial, delinquent behaviour and use of drugs and alcohol.
Of course, the multimodal treatment must also involve the teachers. In deciding on the therapy to perform, the clinician must bear two basic parameters in mind: the age of the child and the severity of the disorder. In the preschool age from 3 to 6 years, diagnosis is possible even through difficult.
The clinician has limited intervention methods at his disposal because of the impossibility of cognitive-behavioural training, effective only after 7 years of age, since in the younger ages the cognitive structures on which they act are not yet mature. Many studies claim that pharmacological treatment is not effective before the age of six. The long-term effects of the psychostimulating medications used to treat ADHD is not yet known; the physician must therefore be very punctilious when administering these medications to children under the age of six. In this age group only psycho-educational treatments can be performed (Table 6) together with the parents and teachers. Between the ages of six and eight, in serious cases or where the psycho-educational treatment with the help of the teachers has not solved the problem, a pharmacological therapy can be started, effective in 70% of cases. If combining psycho-educational treatment and parent training, the percentage rises by as much as 4-5%. For children older than eight, the range of treatments is completed with the cognitive-behavioural therapy, specific training in self-control, and individual or group self-reflection. Pharmacological treatment must be extended over a long period of time.

The MTA study - coordinated by NIMH and conducted for 14 months on 579 ADHD children between the ages of 7 and 9 - compared the results of the various treatments showing 68% positive results in pharmacological treatment in combination with cognitive-behavioural therapy against 25% of standard paediatrician treatment, 34% of cognitive/behavioural therapy and 56% of isolated pharmacological treatment. It was also demonstrated that the later treatment is started the longer it must be performed.
The most effective medications are those that act on the dopamine synapse, such as Methylphenidate, or noradrenergic medications, such as Atomoxetine, which increase the availability of dopamine. The dosage and the number of administrations per day increase with age and body weight. Gradual and personalised titration of the drug is necessary in order to establish the MINIMUM EFFECTIVE DOSE. The efficacy is conditioned by the context, and the severe forms respond really well.
It is unclear whether the associated symptoms increase or decrease the efficacy, but it is certain that Methylphenidate improves and reduces the symptoms associated with anxiety, depression and oppositional defiant disorder. Of course, the efficacy and the side effects (Table 7) must always be closely monitored and the benefits/risks that may affect weight and height must be carefully weighed. The child may initially lose about 2-3 kg because of decreased appetite, but this stabilises over time, and have a reduced annual growth of about 1-1.5 cm.
Most of the undesired side effects are transitory: the most common side effects of psycho-stimulants are headaches, anxiety, crying spells, irritability, stomach aches, insomnia, decreased appetite, reduced growth, dizziness; the side effects of noradrenergic medications are decreased appetite, dizziness, dermatitis, dyspepsia, EEG abnormalities.
THERE IS NO EVIDENCE that the use of stimulants to treat ADHD children leads to use or increased use/abuse of substances in adolescence.
To prevent abuse or addiction to Methylphenidate, which has occurred in America and Europe, Italy has decided to enter all the prescription drugs in a special NATIONAL REGISTER which ties the prescription of Methylphenidate to a half-yearly therapeutic plan by the reference centre. The knowledge of neuropsychological functioning of an ADHD child has in this decade been extremely important in defining the syndrome as a chronic disorder requiring long-term treatment.
The multimodal treatment programme must be personalised and continuously monitored and optimised. Together with psycho-education it constitutes the basis for all ADHD treatments.
Effective interventions include behavioural therapy for the child and his or her family at school and at home. In many cases, pharmacological treatment of the child plays a key role in creating those balanced conditions that allow the child to cooperate.
The challenge is to all pull together - family, clinics and teachers - to achieve psycho-physical well-being of the child. It would be a grave error to dispute the existence of the syndrome and demonise the therapy.
The real challenge is to recognise these children's talents "behind the histrionics of the ADHD symptoms" and to use the family as "resource" to together with the doctors, psychologists, teachers, educators and trainers build a "new" culture of "diversity" where diplomacy is integrated and the border between who helps and who is helped disappears.

Antonella Marcelli
First level medical director at the material and
child health department of asur
Marche - Pesaro
Contract Professor at the University Urbino