ADHD - Atention deficiency and hiperactivity disorder

ADHD

Epidemiology

The Centers for Disease Control and Prevention

(2005) conducted the National Survey of Children’s

Health during January 2003Y2004, asking parents of

more than 100,000 children ages 4 to 17 years whether

their child had ever been diagnosed with ADHD or

received medication treatment (as opposed to currently

being treated). The rate of lifetime childhood diagnosis

of ADHD was 7.8%, whereas 4.3% (or only 55% of

those with ADHD) had ever been treated with

medication for the disorder

Although only

40% of 18- to 20-year-old Bgrown up^ ADHD

patients met the full criteria for ADHD

Comorbidities

Studies have shown that 54%Y84% of

children and adolescents with ADHD may meet criteria

for oppositional defiant disorder (ODD); a significant

portion of these patients will develop conduct disorder

Etiology

Specifically, a meta-analysis of

83 studies with more than 6,000 subjects showed that

patients with ADHD have impairments in the executive

functioning domains of response inhibition, vigilance,

working memory, and some measures of planning.

Faraone et al. (2005b) reviewed 20 independent

twin studies that estimated the heritability (the

amount of phenotypic variance of symptoms attributed

to genetic factors) to be 76%.

Faraone et al. (2005b) identified eight genes in which

the same variant was studied in three or more studies;

seven of which showed statistically significant evidence

of association with ADHD (the dopamine 4 and 5

receptors, the dopamine transporter, the enzyme

dopamine "-hydroxylase, the serotonin transporter

gene, the serotonin 1B receptor, and the synaptosomalassociated

protein 25 gene).

Screening

The clinician should perform a detailed interview with

the parent about each of the 18 ADHDsymptoms listed in

DSM-IV. For each symptom, the clinician should

determine whether it is present as well as its duration,

severity, and frequency

Children suffering a severe head injury may develop

symptoms of ADHD, usually of the inattentive

subtype. Hyperthyroidism,

which can be associated with hyperactivity and

agitation, rarely presents with ADHD symptoms

alone but with other signs and symptoms of excessive

thyroid hormone levels.

Academic impairment is commonly due to the ADHD

itself. However, if there is no clear evidence of an

improvement in academic performance in 1 to 2 months

despite improvement of the ADHD, then psychological

testing for learning disorders is indicated

Treatment

It is also clear that behavior therapy alone

can produce improvement in ADHD symptoms

relative to baseline symptoms or to wait-list controls

Jadad et al. (1999)

reviewed 78 studies of the treatment of ADHD; six of

these studies compared pharmacological and nonpharmacological

interventions. The reviewers reported that

studies consistently supported the superiority of

stimulant over the nondrug treatment. Twenty studies

compared combination therapy with a stimulant or

with psychosocial intervention, but no evidence of an

additive benefit of combination therapy was found.

In the MTA study, children with ADHD were

randomized to four groups: algorithmic medication

treatment alone, psychosocial treatment alone, a

combination of algorithmic medication management

and psychosocial treatment, and community treatment.

Algorithmic medication treatment consisted of

monthly appointments in which the dose of medication

was carefully titrated according to parent and teacher

rating scales. Children in all four treatment groups

showed reduced symptoms of ADHD at 14 months

relative to baseline. The two groups that received

algorithmic medication management showed a superior

outcome with regard to ADHD symptoms compared

with those that received intensive behavioral treatment

alone or community treatment (MTA Cooperative

Group, 1999a [rct]).

Behavior therapy may be

recommended as an initial treatment if the patient’s

ADHD symptoms are mild with minimal impairment,

the diagnosis of ADHD is uncertain, parents reject

medication treatment, or there is marked disagreement

about the diagnosis between parents or between parents

and teachers.

Treatment

The physician is free to choose any of the two

stimulant types (MPH or amphetamine) because

evidence suggests the two are equally efficacious in

the treatment of ADHD.

Single daily dosing is associated with greater

compliance for all types of medication, and long-acting

MPH may improve driving performance in adolescents

relative to short-acting MPH (Cox et al., 2004 [rct]).

Physicians may use long-acting forms as initial

treatment; there is no need to titrate to the appropriate

dose on short-acting forms and then Btransfer^ children

to a long-acting form. Short-acting stimulants are often

used as initial treatment in small children (<16>

weight), for whom there are no long-acting forms in a

sufficiently low dose.

On average, there is

a linear relationship between dose and clinical response:

that is, in any group of ADHD subjects, more subjects

will be classified as responders and there is a greater

reduction in symptoms at the higher doses of stimulant.

There is no evidence of a global Btherapeutic^ window

in ADHD patients. Each patient, however, has a unique

dose-response curve.

After selecting the starting dose, the physician may

titrate upward every 1 to 3 weeks until the maximum

dose for the stimulant is reached, symptoms of ADHD

remit, or side effects prevent further titration, whichever

occurs first

Eight of the nine studies supported the efficacy of MPH

in the treatment of preschoolers with ADHD at

milligram-per-kilogram doses that were comparable

with those used in school-age children

Of note, only 37 of 279 enrolled

parents thought that the behavior training resulted in

significant or satisfactory improvement

Results from the short-term, open-label, run-in and

double-blind, crossover studies do show that MPH is

effective in preschoolers with ADHD (Greenhill et al.,

2006a). The mean optimal dose of MPH was found to

be 0.7 T 0.4 mg/kg/day, which is lower than the mean

of 1.0 mg/kg/day found to be optimal in the MTA

study with school-age children

Atomoxetine is a noradrenergic reuptake inhibitor

that is superior to placebo in the treatment of ADHD in

children, adolescents, and adults

Michelson et al. (2002) showed that although

atomoxetine was superior to placebo at week 1 of the

trial, the greatest effects were observed at week 6,

suggesting the patient should be maintained at the full

therapeutic dose for at least several weeks to obtain the

drug’s full effect. At the end of the treatment period,

atomoxetine led to a significant reduction in ratings of

symptoms of both ADHD and anxiety relative to

placebo, showing the drug to be efficacious in the

treatment of both conditions.

in a meta-analysis of atomoxetine and stimulant studies,

the effect size for atomoxetine was 0.62 compared with

0.91 and 0.95 for immediate-release and long-acting

stimulants, respectively

Bupropion is a noradrenergic antidepressant

that showed modest efficacy in the treatment of

ADHD in one double-blind, placebo-controlled trial

(Conners et al., 1996 [rct]). It is contraindicated in

patients with a current seizure disorder. It can be given in

either immediate-release or long-acting form, but may

not come in pill sizes small enough for children who

weigh <25>

A

gradual titration is required and clinical consensus

suggests the !-agonists are more successful in treating

hyperactive/impulsive symptoms than inattention

symptoms, In recent years clinical consensus has led to the use of clonidine as adjunctive therapy to treat tics

or stimulant-induced insomnia rather than as a primary

treatment for ADHD.

For stimulant medications, the most common side

effects are appetite decrease, weight loss, insomnia, or

headache. Less common side effects of stimulants

include tics and emotional lability/irritability.

If the patient’s ADHD

symptoms respond adequately only to a stimulant

medication that induces tics, then combined pharmacotherapy

of the stimulant and an !-agonist (clonidine

or guanfacine) is recommended (Tourette’s Syndrome)

Controlled trials of stimulants do not support the

widespread belief that stimulant medications induce

aggression. Indeed, overall aggressive acts and antisocial

behavior decline when ADHD patients are treated with

stimulants

In 12 controlled trials involving

1,357 patients taking atomoxetine and 851

taking placebo, the average risk of suicidal thinking

was 4/1,000 in the atomoxetine-treated group versus

none in those taking placebo.

examined all of the available

data and concluded that stimulant treatment may be

associated with a reduction in expected height gain, at

least in the first 1 to 3 years of treatment

CONGENITAL SYPHILIS

CLINICAL MANIFESTATIONS.

Primary syphilis is characterized by syphilitic chancre and regional lymphadenitis. A painless papule appears at the site of inoculation 2–6 wk after inoculation with T. pallidum. The papule soon develops into a clean, painless ulcer with raised borders called a chancre. The chancre, usually on the genitals, contains viable T. pallidum and is highly contagious. Extragenital chancres can be seen also, depending on the site of primary inoculation. Adjacent lymph nodes are generally enlarged. The chancre heals spontaneously within 4–6 wk, leaving a thin scar.

Untreated patients develop manifestations of secondary syphilis 2–10 wk after the chancre heals. Manifestations of secondary syphilis are related to spirochetemia and include a nonpruritic maculopapular rash, which can cover the entire body, and notably involving the palms and soles ( Fig. 215-2 ). Pustular lesions may also develop. Condylomata lata, which are gray-white to erythematous wartlike plaques, can occur in moist areas around the anus and vagina, and white plaques called mucous patches may be found in mucous membranes. A flulike illness with low-grade fever, headache, malaise, anorexia, weight loss, sore throat, myalgias, arthralgias, and generalized lymphadenopathy is often present. Renal, hepatic, and ophthalmologic manifestations may be present, as may be meningitis, which occurs in 30% of patients with secondary syphilis, manifested by cerebrospinal fluid (CSF) pleocytosis and elevated protein level, although the patient may not show neurologic symptoms. Secondary infection becomes latent within 1–2 mo after the onset of the rash. Relapses with secondary manifestations can occur during the 1st year of latency, a period referred to as the early latent period. No relapses occur after the 1st year. What follows is late syphilis, which may be either asymptomatic (late latent) or symptomatic (tertiary). At this stage, patients may begin showing the manifestations of tertiary disease, which include neurologic, cardiovascular, and gummatous lesions. The lesions are granulomas of the skin and musculoskeletal system resulting from the host's delayed hypersensitivity reaction

Congenital Infection.

Untreated syphilis during pregnancy has a transmission rate approaching 100%. Fetal or perinatal death occurs in 40% of affected infants. Among survivors, manifestations have traditionally been divided into early and late stages. The early signs appear during the 1st 2 yr of life, and late signs appear gradually during the 1st 2 decades. Early manifestations result from transplacental spirochetemia and are analogous to the secondary stage of acquired syphilis. Approximately 66% of infected infants are asymptomatic at the time of birth and are identified only by routine prenatal screening; if they are untreated, symptoms develop within weeks or months.

The early manifestations of congenital infection are varied and involve multiple organ systems ( Table 215-1 ). Hepatosplenomegaly, jaundice, and elevated liver enzymes are common. Histologically, liver involvement includes bile stasis, fibrosis, and extramedullary hematopoiesis. Lymphadenopathy tends to be diffuse and to resolve spontaneously, although shotty nodes may persist. Coombs negative hemolytic anemia is characteristic. Thrombocytopenia is often associated with platelet trapping in an enlarged spleen. Characteristic osteochondritis and periostitis ( Fig. 215-3 ) and mucocutaneous rash ( Fig. 215-4 ), pre senting with erythematous maculopapular or bullous lesions, followed by desquamation involving hands and feet, are common. Mucous patches, rhinitis (snuffles), and condylomatous lesions ( Fig. 215-5 ) are highly characteristic features of mucous membrane involvement in congenital syphilis. Bone involvement occurs frequently. Roentgenographic abnormalities include multiple sites of osteochondritis at the wrists, elbows, ankles, and knees, and periostitis of the long bones and rarely the skull. The osteochondritis is painful and often results in irritability and refusal to move the involved extremity (pseudoparalysis of Parrot). Central nervous system (CNS) abnormalities, failure to thrive, chorioretinitis, nephritis, and nephrotic syndrome may also be seen. Clinical manifestations of renal involvement include hypertension, hematuria, proteinuria, hypoproteinemia, hypercholesterolemia, and hypocomplementemia. They appear to be related to glomerular deposition of circulating immune complexes. Less common clinical manifestations of early congenital syphilis include gastroenteritis, peritonitis, pancreatitis, pneumonia, eye involvement (glaucoma and chorioretinitis), nonimmune hydrops, and testicular masses.

TABLE 215-1 -- Clues That Suggest a Diagnosis of Congenital Syphilis^[*]

EPIDEMIOLOGIC BACKGROUND	CLINICAL FINDINGS
Untreated early syphilis in the mother	Osteochondritis, periostitis
Untreated latent syphilis in the mother	Snuffles, hemorrhagic rhinitis
An untreated mother who has contact with a known syphilitic during pregnancy	Condylomata lata
	Bullous lesions, palmar/plantar rash
Mother treated for syphilis during pregnancy with a drug other than penicillin	Mucous patches
	Hepatomegaly, splenomegaly
Mother treated for syphilis during pregnancy without follow-up to delivery	Jaundice
	Nonimmune hydrops fetalis
	Generalized lymphadenopathy
	Central nervous system signs; elevated cell count or protein in cerebrospinal fluid
	Hemolytic anemia, diffuse intravascular coagulation, thrombocytopenia
	Pneumonitis
	Nephrotic syndrome
	Placental villitis or vasculitis (unexplained enlarged placenta)
	Intrauterine growth restriction

The late manifestations result primarily from chronic inflammation of bone, teeth, and the CNS. Skeletal changes due to persistent or recurrent periostitis and associated thickening of bone include frontal bossing, a bony prominence of the forehead(olympian brow), unilateral or bilateral thickening of the sternoclavicular third of the clavicle (clavicular or Higouménaki sign), an anterior bowing of the midportion of the tibia (saber shins), and convexity along the medial border of the scapula (scaphoid scapula). Dental abnormalities are common and include Hutchinson teeth ( Fig. 215-6 ), which are the peg or barrel-shaped upper central incisors that erupt during the 6th yr of life; abnormal enamel, which results in a notch along the biting surface; and mulberry molars, the abnormal 1st lower (6 yr) molars characterized by a small biting surface and an excessive number of cusps. Defects in enamel formation lead to repeated caries and eventual tooth destruction.

A saddle nose ( Fig. 215-7 ), a depression of the nasal root, is a result of syphilitic rhinitis that destroys the adjacent bone and cartilage. A perforated nasal septum may be an associated abnormality. Rhagades are linear scars that extend in a spokelike pattern from previous mucocutaneous fissures of the mouth, anus, and genitalia. Juvenile paresis, an uncommon latent meningovascular infection, typically presents during adolescence with behavioral changes, focal seizures, or loss of intellectual function. Juvenile tabes with spinal cord involvement and cardiovascular involvement with aortitis are extremely rare.

Other late manifestations of congenital syphilis may represent a hypersensitivity phenomenon. These include unilateral or bilateral interstitial keratitis with symptoms such as intense photo phobia and lacrimation, followed within weeks or months by corneal opacification and complete blindness. Less common ocular manifestations include choroiditis, retinitis, vascular occlusion, and optic atrophy. Eighth nerve deafness may be unilateral or bilateral, appears at any age, presents initially as vertigo and high-tone hearing loss, and progresses to permanent deafness. The Clutton joint represents a unilateral or bilateral synovitis involving the lower extremities (usually the knee), which presents as painless joint swelling with sterile synovial fluid; spontaneous remission usually occurs after a period of several weeks. Soft tissue gummas (identical to those of acquired disease) and paroxysmal cold hemoglobinuria are rare hypersensitivity phenomena.

Diagnosis of primary syphilis is confirmed when T. pallidum is demonstrated by dark-field microscopy or direct fluorescent antibody–T. pallidum testing on specimens from skin lesions, placenta, or umbilicus. Nontreponemal tests, which are the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests, detect antibodies against phospholipid antigens on the surface of treponeme that cross react with mammalian cardiolipin antigens. The nontreponemal tests usually become nonreactive within 1 yr of adequate therapy for primary syphilis and within 2 yr of adequate treatment for secondary disease. With congenital infection, these tests become nonreactive within a few months after adequate treatment. Treponemal tests, which measure antibody specific for T. pallidum, include the T. pallidum hemagglutination assay (TPHA), the fluorescent treponemal antibody absorption (FTA-ABS) test, and the T. pallidum particle agglutination (TPPA) test. Treponemal tests are used for confirmatory testing of positive results of the nontreponemal antibody tests. Treponemal antibody titers become positive soon after initial infection and usually remain positive for life, even with adequate therapy. These antibody titers do not correlate with disease activity and are not quantified. They are useful for diagnosis of a 1st episode of syphilis and for distinguishing false-positive results of nontreponemal antibody tests but are of limited usefulness in the evaluation of response to therapy and possible reinfections. The nontreponemal tests (VDRL, RPR) are uniformly nonreactive in Lyme disease. Passively acquired antibody is suggested by neonatal titer at least 4-fold (i.e., a 2-tube dilution) less than the maternal titer. The diagnosis of neurosyphilis is established by demonstrating pleocytosis and increased protein in the CSF, and a positive CSF VDRL test along with neurologic symptoms. The CSF VDRL test is very specific but relatively insensitive (22–69%) for neurosyphilis.

Symptomatic infants should be thoroughly evaluated (see Table 215-1 ) and treated. Asymptomatic infants considered at risk for congenital syphilis because the maternal nontreponemal and treponemal serology is positive should be evaluated if (1) maternal treatment was inadequate, unknown, or undocumented; (2) maternal treatment was ≤30 days before delivery; (3) the mother was treated with erythromycin or another nonpenicillin regimen; or (4) the maternal nontreponemal titers did not decrease sufficiently to demonstrate a cure (4-fold or greater). If the maternal treatment was adequate and ≥1 mo before delivery, the infant's positive nontreponemal test result represents passively acquired antibody and the infant does not need treatment at delivery, but follow-up serology should be obtained. If the maternal evaluation is incomplete, these infants are assumed infected and treated.

TABLE 215-2 -- Recommended Treatment of Neonates (≤4 wk of age) With Proven or Possible Congenital Syphilis

CLINICAL STATUS	EVALUATION	ANTIMICROBIAL THERAPY[*]
Proven or highly probable disease[†]	CSF analysis for VDRL, cell count, and protein	Aqueous crystalline penicillin G, 100,000–150,000 U/kg/day, administered as 50,000 U/kg/dose IV every 12 hr during the 1st 7 days of life and every 8 hr thereafter for a total of 10 days
	CBC and platelet count
	Other tests as clinically indicated (e.g., long bone radiography, liver function tests, ophthalmologic examination)
		OR
		Penicillin G procaine,[‡] 50,000 U/kg/day IM in a single dose for 10 days
Normal physical examination and serum quantitative nontreponemal titer the same or <4-fold>
(a) (i) Mother was not treated or inadequately treated or has no documented treatment;(ii) mother was treated with erythromycin or other nonpenicillin regimen;(iii) mother received treatment ≤4 wk before delivery	CSF analysis for VDRL, cell count, and protein	Aqueous crystalline penicillin G IV for 10 days[‡]
	CBC and platelet count	OR
	Long bone radiography	Penicillin G procaine,[‡] 50,000 U/kg/day IM in a single dose for 10 days[§]
		OR
		Penicillin G benzathine, 50,000 U/kg IM in a single dose[§]
(b) (i) Adequate maternal therapy given >4 wk before delivery;(ii) mother has no evidence of reinfection or relapse	None	Clinical, serologic follow-up, and penicillin G benzathine, 50,000 U/kg IM in a single dose[∥]
(c) Adequate therapy before pregnancy and mother's nontreponemal serologic titer remained low and stable during pregnancy and at delivery	None	None[¶]

The diagnosis of neurosyphilis in the newborn with syphilitic infection is difficult owing to the poor sensitivity of the CSF VDRL test in this age group and the lack of CSF abnormalities. A positive CSF VDRL test result in a newborn warrants treatment for neurosyphilis, even though it might reflect passive transfer of antibodies from serum to CSF. More importantly, it is now accepted that all infants with a presumptive diagnosis of congenital syphilis should be treated with regimens effective for neurosyphilis because this cannot be reliably excluded.

TABLE 215-3 -- Recommended Treatment for Syphilis in People >4 Weeks of Age

	CHILDREN	ADULTS
Congenital syphilis	Aqueous crystalline penicillin G, 200,000–300,000 U/kg/day IV administered as 50,000 U/kg every 4–6 hr for 10 days[*]
Primary, secondary, and early latent syphilis[†]	Penicillin G benzathine,[‡] 50,000 U/kg IM up to the adult dose of 2.4 million U in a single dose	Penicillin G benzathine, 2.4 million U IM in a single dose
		OR
		If allergic to penicillin and not pregnant, Doxycycline, 100 mg orally twice a day for 14 days
		OR
		Tetracycline, 500 mg orally 4 times/day for 14 days
Late latent syphilis[§] or latent syphilis of unknown duration	Penicillin G benzathine, 50,000 U/kg IM up to the adult dose of 2.4 million U, administered as 3 single doses at 1 wk intervals (total 150,000 U/kg, up to the adult dose of 7.2 million U)	Penicillin G benzathine, 7.2 million U total, administered as 3 doses of 2.4 million U IM each at 1 wk intervals
		OR
		If allergic to penicillin and not pregnant, Doxycycline, 100 mg orally twice a day for 4 wk
		OR
		Tetracycline, 500 mg orally 4 times/day for 4 wk
Tertiary	—	Penicillin G benzathine, 7.2 million U total, administered as 3 doses of 2.4 million U IM at 1 wk intervals
		If allergic to penicillin and not pregnant, same as for late latent syphilis
Neurosyphilis[∥]	Aqueous crystalline penicillin G, 200,000 to 300,000 U/kg/day, given every 4–6 hr for 10–14 days in doses not to exceed the adult dose	Aqueous crystalline penicillin G, 18–24 million U/day, administered as 3–4 million U IV every 4 hr for 10–14 days[¶]
		OR
		Penicillin G procaine,[†] 2.4 million U IM once daily PLUS probenecid, 500 mg orally 4 times/day, both for 10–14 days[¶]

Prevention

In pregnant women without optimal prenatal care, serologic screening for syphilis should be performed at the time pregnancy is diagnosed. Any woman who is delivered of a stillborn infant ≥20 wk of gestation should be tested for syphilis. In communities and populations with a high prevalence of syphilis, or for patients at high risk, testing should be performed at least 2 additional times: at the beginning of the 3rd trimester (28 wk) and at delivery