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Psychomicrobiology

The Potential Role of Infections in AttentionDeficit Hyperactivity Disorder Malhotra S*, Bhatia NK*, Kumar P**, Hans C*, Bhatia MS*** Department of Microbiology*, RML Hospital and PGIMER, New Delhi; CCRUM** New Delhi; Department of Psychiatry***, UCMS & G.T.B. Hospital, Delhi University, Dilshad Garden, Delhi-110095

ABSTRACT Attention deficit hyperactivity disorder ADHD is a behavioral disorder which mostly affects children in the age group of six to eleven years. The disorder affects boys more than girls. Although difficult to assess in infancy and toddlerhood, signs of ADHD may begin to appear as early as age of two or three, but the symptom picture changes as adolescence approaches. Many symptoms, particularly hyperactivity, diminish in early adulthood. However, impulsivity and inattention problems remain with upto 50% of ADHD individuals through their adult life. Recently there have been studies on correlation between ADHD and bacterial and viral infections in brain. This review focuses on possible role of various viruses and certain bacterias in development of ADHD in children. Introduction Attention-Deficit/Hyperactivity disorder (ADHD) is a developmental disorder characterized by distractibility, hyperactivity, impulsive behaviors, and the inability to remain focused on tasks. It affects 5% or more of school children. The National Institutes of Health (NIH) regards ADHD as the most commonly diagnosed behavioral disorder of childhood and hence, a major public health problem. Epidemiology ADHD also known as hyperkinetic disorder (HKD) affects approximately 2 million children in USA The condition afflicts boys more often than girls. Some children suffer primarily from inattentiveness rather than from hyperactivity and are classified as having Attention Deficit Disorder (ADD).1 Studies done in Japan, China, Germany, France, Holland, Sweden and North America suggest that 3-9% of children are affected. Although difficult to

assess in infancy and toddlerhood, signs of ADHD may begin to appear as early as age 2 or 3. Children with ADHD have short attention spans, becoming easily bored or frustrated with tasks. Although they may be quite intelligent, their lack of focus frequently results in poor grades and difficulties in school. ADHD children act impulsively, taking action first and thinking later. They constantly move, run, climb, squirm, and fidget, but often have trouble with gross and fine motor skills. Their clumsiness may extend to the social arena, where they are sometimes shunned due to their impulsive and intrusive behavior 2 . Many symptoms, particularly hyperactivity, diminish in early adulthood, but impulsivity and inattention problems remain with upto 50% of ADHD individuals throughout their adult life. Etiology The causes of ADHD are not completely known. Certain studies have been performed to understand the etiology:

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a) Genetic Studies There is no evidence to suggest that ADHD is due to chromosomal abnormalities of structure, fragility or the presence of extra material but different lines of research strongly suggest that it is a highly hereditary condition. Genetic factors account for approximately 80% of etiology of ADHD3 b) Family aggregation studies Between 10 to 35% of immediate family members of ADHD children are also likely to have ADHD, for siblings the figure is about 32%, and if a parent has ADHD the risk to offspring is 57%.4 c) Twin studies These support the notion that ADHD runs in families.5 d) Molecular genetics Some studies have been done attempting to find the gene/ genes responsible. Studies on two dopamine sites (the dopamine transporter and the D4 receptor) have shown an association with ADHD6 f) Neuropsychology and Other Studies A large number of studies have shown deficits on neuropsychological tests of frontal lobe functions. Results point to disinhibition of behavioral responses, difficulties with working memory, planning and other functions of the frontal lobe.2,5 On continuous performance task (CPT) tests, ADHD children make more errors than control children when performing tasks. The control children show increased frontal activation, especially in the right prefrontal region, on task performance. Children with ADHD show a lower level of such activation. Differences between children with and without ADHD have been found on quantitative electroencephalography (QEEG) testing. Children with ADHD show elevated theta (slow wave) activity in the frontal regions. g) Complications of Pregnancy and Birth Some studies have found a slightly increased incidence of unusually short or long labor, fetal distress, low forceps delivery and eclampsia. In addition low 362

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birth weight, and birth injuries, has been associated with an increased risk of ADHD behaviors.2,7,8 One study showed season of birth to be a risk factor, so it has been postulated that this is related to the incidence of seasonal viral infections. The authors concluded that “exposure to winter infections during the first trimester may account for some subtypes of ADHD. They refer in particular to a statistically significant peak in September births for children with ADHD and co morbid learning disorders (Northern Hemisphere). A 1999 various studies looked at pre and perinatal striatal injury as a possible cause of ADHD and found that that perinatal adverse events may play a role in the pathogenesis of some cases of ADHD.7,8 Finally, in a paper published in the Journal of Child Neurology looking at brain anomalies in ADHD children on MRI scan the authors concluded that early brain development could play a role in ADHD pathophysiology, and stated that: “the etiology of ADHD could be conceptualized as a genetically vulnerable brain that is subject to an environmental insult during early brain development and leading to aberrations in brain structure and function.”2 h) Toxins (i) Lead Elevated body lead has been shown to have a “small but consistent and statistically significant relationship” to ADHD symptoms.9 (ii) Tobacco and alcohol (prenatal exposure): There is some relationship between prenatal exposure to tobacco and alcohol and inattention and hyperactivity, however like lead it is currently only correlational. There are confounding variables here. For example, does the woman who smokes in pregnancy and has an ADHD child have ADHD herself.10 It is estimated that as with lead most studies on these substances have not evaluated or controlled for the presence of ADHD in the

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parents. However, there is one paper in which the authors found: “a strong and significant positive association between smoking by mothers during pregnancy and ADHD in their children that could not be attributed to socioeconomic status, parental ADHD and parental IQ”.8 ADHD and Infections (Bacterial and Viral) – Is there a Link? Reports of a seasonal pattern of birth for subtypes of ADHD suggest an association with seasonally mediated viral infections. In a study of 140 boys with ADHD and 120 normal controls, September births were significantly correlated with ADHD and learning disability (odds ratio: 5.4). A trend toward an increase in winter births was also evident. Exposure to viral infections during winter months in the first trimester of fetal life or at the time of birth may be a predisposing factor in 10% of subjects with ADHD with co morbid learning disabilities.11 Viral infections during pregnancy, at birth, and in early childhood have been linked to an increased risk of developing ADHD. In a casecontrol study in Italy, children born to women who had a viral exanthematous rash during pregnancy had an increased risk of ADHD. Measles, varicella, or rubella was reported by 4 of 71 mothers of children with ADHD and none of the 118 control mothers (p < 0.01). The difference was significant after adjusting for other potential risk factors.12 Other viral infections associated with an increased prevalence of ADHD and learning disorders included HIV, enterovirus 71, and varicella zoster encephalitis. Herpes simplex virus antibodies showed no significant correlation with ADHD or other neuropsychiatric disorders.13 Febrile seizures, frequently associated with human herpes virus 6 in the United States and with influenza A in Asia are a risk factor for subsequent development of hyperactive behavior and ADHD.14-16 Influenza Virus Since the initial report of an influenzaassociated postencephalitic behavior disorder,17 influenza viral infection as a potential cause of ADHD has received little attention.18 A literature search uncovered only one influenza-related ADHD epidemiologic study that showed frequency of

health care utilization for influenza and ADHD.19 Data from the National Ambulatory Medical Care Survey (1996–2001) showed that rural children 5 to 9 years old were seen more frequently than nonrural children for treatment of ADHD (p < .001) and influenza (p < .037). HIV Infection Among 274 previously treated HIV-infected children aged 2 to 17 years, the most common behavioral problems, as measured by the Conners’ Parent Rating Scale, were learning (25%), hyperactivity (20%), impulsive hyperactive (19%), conduct (16%), and anxiety (8%). Mean Wechsler Intelligence Scale for Children- III scores were less than average norms, and hyperactivity was more frequent in children with a performance IQ of 90.44.20 Enterovirus 71 Infection Enterovirus 71 infection with central nervous system involvement may be associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning. Of 47 patients who were recovering from enterovirus 71 aseptic meningitis or encephalitis and attending school, 6 (13%) had ADHD and required medication, and 3 were in special education.21 Varicella Zoster Encephalitis A patient with encephalitis caused by primary varicella zoster infection developed ADHD and a tic disorder. MRI studies localized the encephalitis to the basal ganglia.22 Borrelia burgdorferi is the spirochete that causes Lyme disease; it has numerous psychiatric and neurologic presentations, including ADHD.23 Streptococcal Infections Pediatric autoimmune neuropsychiatric disorders associated with group A β-hemolytic streptococcal infections, in addition to obsessivecompulsive disorder and tic disorders, include hyperactive behavior, cognitive deficits, and oppositional behaviors. Symptom onset and exacerbations of ADHD seem to be triggered by streptococcal infection according to some reports.24,25 In contrast, a more recent study that examined the temporal relationship between newly acquired streptococcal infections and acute

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exacerbations of tic and obsessive compulsive disorders revealed no clear correlation.26 A possible relation between ADHD and streptococcal infection requires confirmation. Otitis Media In preschool-aged children, otitis media was linked to hyperactive behavior and/or inattention, independent of learning disability, in 21 of 138 children evaluated in a child development clinic. Children with ADHD had significantly more complaints of earaches during the preceding 3 months and year of observation.27 An analysis of a total of 7 articles obtained through PubMed and published between 1978 and 1999 revealed a positive association between a history of recurrent otitis media and subsequent development of typical ADHD in only 1 study; hyperactive behavior was reported in 4, combined with language and/or learning disorders in 2, and speech, language, and learning deficits in 2 patient groups. The studies were retrospective in design, and each involved between 18 and 507 children. Although typical ADHD seems to have a weak association with otitis media, some researchers consider a history of significant middle-ear disease in early childhood to be a risk factor for hyperactivity and especially speech and language disorders in children who present with learning problems in school.28 Postencephalitis and Postmeningitis Hydrocephalus Viral encephalitis and meningitis of bacterial (including tubercular) or non-bacterial origin is a common and lethal complication of CNS in children, which may lead to hydrocephalus. These children may present with symptoms suggestive of ADHD and they do not respond to traditional treatment.30 Effective use of appropriate antibiotics and shunt procedures are appropriate treatment. Diagnosis In a 1999 consensus statement on ADHD, the National Institutes of Health acknowledged that years of clinical research had yielded only speculation about the causes of the condition. Since the causes are not known, there is no definitive program for preventing ADHD. However, psychologists have experimented with early 364

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intervention for ADHD children. Using the theory that speech and motor functioning are linked to the ability to pay attention and concentrate, child psychologists set up an early intervention program that offered occupational therapy and speech therapy to preschoolers. The children were reevaluated when they were 8 to 10 years old and there was a small difference between ADHD and non-ADHD children, but it was not statistically significant. However, when psychologists factored in a family history of ADHD, the early intervention did make a difference. Although the research is still in the early stages, it gives scientists a promising direction for additional study. The first step in determining if a child has ADHD is to consult with a pediatrician. The pediatrician can make an initial evaluation of the child’s developmental maturity compared to other children in his or her age group. The physician should also perform a physical examination to rule out any organic causes of ADHD symptoms, such as an overactive thyroid or vision or hearing problems. If no organic problem can be found, a psychologist, psychiatrist, neurologist, neuropsychologist, or learning specialist is typically consulted to Perform a comprehensive ADHD assessment. Public schools are required by federal law to offer free ADHD testing upon request. Some advocacy groups encourage parents to consult with more than one physician for diagnosis and prescription of medication. Some of the toughest ethical issues center not on the children who are most severely ill but on those with borderline diagnoses. Diagnosis is usually made by subjective observations of behavior at home and in the classroom. Critics charge that some of the yardsticks for ADHD, such as “fidgety, distracted, talking out of turn,” apply to all children at times and are thus meaningless. There is some preliminary research at Stanford University on using magnetic resonance imaging (MRI) to diagnose boys with ADHD, but much more research will be needed before there is a definitive method of diagnosis. For the studies to be scientifically valid, researchers will need to compare the findings on ADHD children against data on children with disorders that are similar to ADHD, and children on Ritalin will need to be compared with children

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who are taking a placebo. Treatment Modalities Psychosocial therapy, usually combined with medications, is the treatment of choice to alleviate ADHD symptoms. Psychostimulants, such as dextroamphetamine, pemoline, and methylphenidate are commonly prescribed to control hyperactive and impulsive behavior and increase attention span.31,32 They work by stimulating the production of certain neurotransmitters in the brain. Possible side effects of stimulants include nervous tics, irregular heartbeat, loss of appetite, and insomnia. In children who do not respond well to stimulant therapy, tricyclic antidepressants such as desipramine and amitriptyline are frequently recommended. 33 Reported side effects of these drugs include persistent dry mouth, sedation, disorientation, and cardiac arrhythmia. Other medications prescribed for ADHD therapy include buproprion, fluoxetine, and carbamazepine. 33 Clonidine, antihypertensive medication (Calcium channel blocker), has also been used to control aggression and hyperactivity in some ADHD children, although it should not be used with methylphenidate. A child’s response to medication will changes with age, so symptoms should be monitored and prescriptions adjusted accordingly. In addition to drugs, behavior modification therapy, which uses a reward system to reinforce good behavior and task completion, can be implemented in the classroom and at home. Behavior modification rewards good behavior until it becomes ingrained. A variation of this technique, cognitive-behavioral therapy, works to decrease impulsive behavior by getting the child to recognize the connection between thoughts and behavior, and to change behavior by changing negative thinking patterns.34 Teachers often work with families and physicians to help provide an atmosphere where the ADHD child can succeed. A teacher might increase the distance between desks, use concise instructions and use shorter assignments or work periods. An ADHD student might be seated in a quiet area close to a good role model or “study buddy”. A teacher might ignore minor inappropriate behavior and praise an ADHD student for raising

his hand to answer a question. Frequently a teacher will work with an ADHD student to develop a private signal to remind the student to stay on task. A number of alternative treatments exist for ADHD. Although there is a lack of controlled studies to prove their efficacy, proponents of alternative treatments report that they are successful in controlling symptoms in some ADHD patients. Some of the more popular alternative treatments include: EEG, biofeedback, dietary therapy, and herbal therapy. The safety of herbal remedies has not been demonstrated in controlled studies. Dietary therapy remains under debate, with some clinicians observing that 70 percent of children who crave sweets have better control over their behavior when following a diet that is low in added sugar. A clinical trial in Britain showed that the majority of ADHD children in a London hospital suffered from food intolerance that was linked to hyperactive behavior. Children with ADHD were most likely to be intolerant of or allergic to foods made with cow’s milk, corn, wheat, soy and eggs. Some patients seek homeopathic medicine as an alternative therapy for ADD and ADHD because it treats the whole person at a core level. Approximately 70-80% of ADHD patients treated with stimulant medication experience significant relief from symptoms, at least in the short-term. About half of ADHD children seem to “outgrow” the disorder in adolescence or early adulthood. The other half will retain some or all symptoms of ADHD as adults. The best treatment for adults with ADHD is still under study. Preliminary research shows that antidepressants may help such adults and they may not require stimulants such as methylphenidate. Research on teenagers and adults who have been treated with methylphenidate is contradictory as to whether methyl-phenidate use predisposes patients to misuse stimulants, alcohol and other drugs as they get older. A small study of adult prisoners showed a much higher incidence of ADHD than in the general public, but much more research is needed.31-34 Complications Untreated, ADHD negatively affects a child’s social and educational performance and can seriously damage his or her sense of self-esteem. ADHD children have impaired relationships with

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their peers, and may be looked upon as social outcasts. They may be perceived as slow learners or troublemakers in the classroom.34 Siblings and even parents may develop resentful feelings toward the ADHD child. Children with ADHD use a large portion of the resources of the health care system, the school system, the criminal justice system and other social service agencies. Some ADHD children also develop a conduct disorder problem. For those adolescents who have both ADHD and a conduct disorder, up to 25% develop antisocial personality disorder and the criminal behavior, substance abuse, and high rate of suicide attempts that are symptomatic of it.2,34 Children diagnosed with ADHD are also more likely to have a learning disorder, a mood disorder such as depression, or an anxiety disorder. It is not unusual for children with ADHD to suffer from obsessive-compulsive disorder (OCD) or Tourette’s syndrome.

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4.

5.

6. 7. 8.

Conclusions The etiology of ADHD is multifactorial. A genetic cause linked to dopamine deficit is frequent and primary, but various environmental factors, including maternal smoking during pregnancy, prematurity, cerebral hypoxic ischemia, alcohol exposure, and nutritional and endocrine disorders may contribute as secondary causes. Chronic viral and bacterial infections play a role in contributing this problem. The etiology is probably a combination of genetic and acquired factors in most cases. The early prenatal recognition, prevention, and treatment of environmental causes may provide more effective management and reduce the reliance on symptom modification with medication. Advice regarding hazards of nicotine and alcohol exposure and monitoring of blood count and thyroid function during pregnancy are particularly important for patients with a family history of ADHD.

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