Echovirus

Author: Jorge M Quinonez, MD, Medical Director of Pediatrics, Chief Medical Officer, Family Health Centers of South West Florida, Inc

 

Introduction

Background

Echoviruses (EVs) are RNA viruses of the genus Enterovirus and the family Picornaviridae. EVs were first isolated from the feces of asymptomatic children early in the 1950s, soon after the development of cell culture techniques. EVs cause cytopathic effects in primate cell cultures, although not initially associated with any disease condition. These orphan viruses were initially termed ECHO, an acronym for enteric cytopathic human orphan virus, which was later simplified to echovirus.
A committee sponsored by the National Foundation for Infantile Paralysis categorized EVs and other enteroviruses (ie, coxsackievirus group A and group B, polioviruses) together in 1957. They are grouped together and distinguished from other viruses on the basis of physicochemical characteristics and because they share common epidemiology, clinical manifestations, and pathogenesis. Enterovirus groups are differentiated based on host specificity. To date, 67 serotypes of enterovirus have been identified, 32 of which belong to the echovirus group.
EVs cause a wide range of common and uncommon clinical presentations. These agents and other members of the Enterovirus group are among the leading causes of acute febrile illness in infants and young children; they are the most common cause of aseptic meningitis. Infection in the first 2 weeks of life is particularly troublesome because it can cause severe systemic disease and is associated with high fatality rates. Another significant concern with enteroviral infections is that they can mimic symptoms caused by other common bacteria and viral infections; thus, enteroviral infections are often treated with therapies aimed for other infections.
EVs are small, measuring 24-30 nanometers (nm) under electron microscopy. They are composed of a naked protein capsid, constituting about 75% of the particle and enclosing a dense central core of single-stranded RNA. This RNA is approximately 7.5 kilobase (kb) long and contains an RNA replicase, viral-coded proteases, a single polyprotein that is responsible for forming structural polypeptides, and other proteins necessary for cellular replication. All EVs contain polypeptide chains (eg, virus protein 1 [VP1], virus protein 4 [VP4]). These structural proteins are important to determine host range and tropism, and they play a crucial role in delivering the RNA genome into the cytoplasm of new host cells.
Although EVs originally were classified into 34 serotypes, EV-10 later was reclassified as a reovirus and EV-28 as rhinovirus type 1; EV-9 now is considered the same as coxsackievirus A23.
At least 2 cellular receptors for EV have been identified: a subunit of the integrin molecule VLA-2 that binds types 1 and 8, and a complement regulatory protein (ie, a decay accelerating factor) that binds types 6, 7, 12, and 21.

Pathophysiology

Some viral replication occurs in the nasopharynx after exposure, with spread to regional lymph nodes. However, most inoculum is swallowed and reaches the lower GI tract, where the virus presumably binds to specific receptors on enterocytes. The virus traverses the intestinal epithelium, probably undergoing replication in the process but without causing any cellular effects, and reaches the Peyer patches in the lamina propria mucosae. Here, the virus undergoes substantial multiplication. A minor viremia develops on about the third day, seeding many secondary infection sites, including the CNS, liver, spleen, bone marrow, heart, and lungs. Additional replication at these sites causes a major viremia that coincides with onset of clinical disease, usually 4-6 days after exposure. The delayed appearance of CNS disease symptoms suggests viral spread can develop during both the minor and the major viremia.
Enteroviruses can infect all tissues of the human body. The tropism of each virus for certain tissues is not well understood and is neither unique nor specific. Infections involving a single serotype may vary widely in their presentation; multiple serotypes can produce the same clinical syndrome.
The incubation period for EV is difficult to establish because both symptomatic and healthy individuals spread the virus. Incubation is believed to range between 2 days and 2 weeks. EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.

Frequency

United States

Several studies confirm enteroviruses account for more than 50% of spring and fall emergency department visits by infants and young children for fever without a source. EV infections only sporadically develop in other seasons. In addition to this seasonality, EV types vary strikingly in their contribution to human disease. Some EVs remain endemic in patterns that vary from area to area each year in the United States. Other serotypes (eg, EV-9, EV-11, EV-30) can cause widespread outbreaks in which the responsible strain can account for more than 90% of all isolated strains of enterovirus.
Infections by this group of viruses are most prevalent among lower socioeconomic groups, a fact easily explained by overcrowded living conditions and poor hygiene.

International

EV infections occur in all human populations. Transmission and infection occur throughout the year in the tropics and predominantly during summer and fall in temperate regions, with sporadic cases in other seasons. A few epidemics have been nearly global, such as one caused by EV-9 at the end of the 1950s and another by EV-11 in 1979 and 1980. More recently, an outbreak of EV-13 and EV-30 was reported in Germany,¹ and outbreaks of EV-13 were reported in Lithuania and Israel.^2,3 An outbreak of EV-11 has also been reported in neonates in Taiwan.⁴ Particular serotypes are endemic or epidemic for unknown reasons. One hypothesis is that some epidemic strains such as EV-9 may spread rapidly in a "critical mass" of susceptible patients necessary for continuous transmission, whereas endemic strains may not be as contagious.

Mortality/Morbidity

EV infections during the first 2 weeks of life can cause severe systemic disease associated with high fatality rates. EV and other enteroviruses account for 10-20% of documented viral causes of encephalitis. Neonates with disseminated encephalitis have a poor prognosis and many die. Infant death rates from perinatal EV infection are unknown, although some studies report high numbers. Neonatal mortality is usually caused by either overwhelming liver failure or myocarditis, rather than CNS involvement.
Children and older patients with disseminated encephalitis have a better prognosis, but fatalities occasionally occur. Acute myopericarditis, resulting from the well-established tropism of enterovirus for the heart, can be fatal in approximately 5% of cases, although most patients recover without major sequelae.

Sex

For unknown reasons, forms of EV disease such as meningitis and neonatal sepsis are far more common among male patients.

Age

Although EV infections can occur in all age groups, incidence inversely relates to age; specific antibodies directly increase with time. Several studies performed during epidemics and for surveillance show that infants become infected at significantly higher rates than older children and adults.

Clinical

History

Because echovirus (EV) has been found in the stools of healthy individuals, most children with EV and other enteroviral infections are assumed to be asymptomatic. Finding the virus in the stools of healthy individuals, however, may be misleading because enterovirus can be excreted in feces for a long time, and no clear indication exists of what happened during the initial infection. Patients may have symptoms with infection, but the symptoms may be trivial and not recognized.

• Nonfocal, acute febrile illness is the most common presentation of symptomatic enteroviral infection in young infants and children.
• Enteroviral infections are the most common cause of hospital admission for suspected sepsis in children aged 2-3 months during summer and fall.

Physical

EV causes a remarkable range of diseases. Benign forms of disease are well recognized by clinicians (eg, nonspecific exanthems, herpangina) and do not warrant major diagnostic or therapeutic actions. Severe forms of disease, such as meningitis, encephalitis, neonatal sepsis, myocarditis, and chronic infection with meningoencephalitis in patients with altered immunity, are strong reasons for concern.

• Nonspecific, acute febrile illness: Several studies have shown enterovirus can account for more than 50% of summer and fall emergency department visits for fever of unknown origin in infants and young children.
  • Fever onset is usually abrupt and without a prodrome, often exceeding 39° C. Fever, which may be the sole presentation, often is accompanied by irritability. High temperatures, irritability, and the nonspecific nature of the illness prompt the hospitalization of many infants for suspected bacterial sepsis. At least 50% of these patients have a history of poor feeding, and 25% of infants have vomiting or diarrhea. Affected infants resume feeding within 2 days of initial symptoms, and their GI manifestations are not the reason for hospital admission.
  • A large number of these patients have had thorough evaluations that included blood, urine, and cerebrospinal fluid (CSF) cultures and have received antibiotics for 48-72 hours while awaiting culture results. Differentiating patients infected with enterovirus from those with bacterial infections is impossible based solely on clinical findings.
  • Most young patients recover from the febrile episode in 2-10 days without complications.
• Exanthems
  • Skin rashes are more common with EV infections than with infections from other enteroviruses. The first exanthematous disease induced by an enterovirus was linked to EV-16.
  • Exanthems may be maculopapular, morbilliform, macular, petechial, or papulopustular in nature.
  • Likelihood of an exanthem being present appears directly related to the EV type causing infection. For example, EV-6, which has been among the most prevalent serotypes causing infection during the past 25 years, is associated only sporadically with skin manifestations. Conversely, infections with EV-5, EV-9, and EV-25 are associated with skin rashes in as many as 35% of patients.
  • Skin findings with EV infections are self-limited and without sequelae.
• Viral meningitis
  • As many as 90% of community-acquired viral meningitis cases result from EVs or coxsackie B viruses. CNS involvement is most likely with infections by EV serotypes 4, 6, 9, 11, 13, 16, and 30. More than 10,000 cases of enteroviral meningitis are reported annually to the Centers for Disease Control and Prevention (CDC), and actual numbers probably are 10 times higher.
  • Infants younger than 3 months have the highest incidence of recognized meningitis. This diagnosis is not based on specific neurological findings; instead, young infants are more likely to undergo a lumbar puncture for evaluation of a fever. Most young children with meningitis present with fever and irritability.
  • Older children with meningitis typically present with fever and severe headache. Headaches in older children and adults can be sufficiently severe to require narcotics for pain control.
  • Nuchal rigidity occurs in less than two thirds of patients and does not occur in infants.
  • Patients can have symptoms of photophobia, nausea, and vomiting.
  • About 10% of hospitalized infants with echoviral meningitis have neurologic manifestations (eg, seizures, altered mental status, increased intracranial pressure).
  • The classic results of CSF analysis are a mononuclear pleocytosis (100-300 cells/mm3), mildly elevated protein levels, and glucose concentrations within reference ranges. Higher WBC counts with a predominance of neutrophils occur early in the course of disease.
  • Illness duration typically is less than a week.
  • Despite current studies of antiviral drug therapies, standard treatments are limited to alleviating symptoms. Although the short-term prognosis appears good for young children with echoviral and other enteroviral meningitis, controversy continues about long-term cognitive, developmental, and language abnormalities among children who suffered meningitis in early life. Some prospective reports have indicated virtually no measurable long-term effects, even among patients who had neurologic findings during their illness.
• Encephalitis
  • Clearly distinguishing encephalitis from enteroviral meningitis is important. Encephalitis is more rare, is a more devastating acute disease, and has long-term sequelae.
  • EV and other enteroviruses account for 10-20% of documented viral-caused encephalitis. Common serotypes that cause encephalitis include EV types 4, 6, 9, 11, and 30. EVs are more commonly associated with a global encephalitis and generalized neurological depression.
  • Clinical manifestations range from altered mental status to coma and decerebration. Some patients manifest with focal disease (eg, partial motor seizures, hemichorea, cerebellar ataxia), symptoms that may suggest a diagnosis of herpes simplex encephalitis. Brain imaging by CT scan or MRI and electroencephalography usually show the extent of involvement. The results of CSF analysis in patients with encephalitis are similar to the results from patients with only aseptic meningitis.
  • The prognosis for neonates with disseminated encephalitis is poor, and many die. The prognosis for similarly affected children and older patients is better, but fatalities sometimes occur.
• Other neurological syndromes
  • Although rare, EV can cause a syndrome of acute motor weakness and paralysis indistinguishable from poliomyelitis. Sporadic cases of acute paralysis have been reported with EV-6 and EV-9. The myelitis caused by EV usually is less severe than that caused by poliovirus.
  • Guillain-Barré syndrome has been associated with EV-6 and EV-22 infections. Acute cerebellar ataxia has been related to infection with EV-6 and EV-9. Acute transverse myelitis has occurred in patients with EV-5 infection.
  • Chronic meningoencephalitis can occur in association with coxsackievirus or EV in patients who have acquired or congenital B-lymphocyte function defects. These patients present with an insidious course, manifested by headache, lethargy, motor dysfunction, or seizures. Symptoms may fluctuate in severity, wane, or gradually progress. Persistent pleocytosis and high protein levels in CSF are typical. Recovery of the virus from several other tissues suggests the possibility of disseminated disease. Prognosis for these patients generally is poor. The results of using intravenous immunoglobulin (IVIG) to treat these patients have been inconsistent.
• Muscle and joint infections
  • EV infections sporadically involve muscles; both focal and generalized myositis has been described. Patients usually present with myalgia associated with elevated levels of skeletal muscle enzymes in serum. The course is self-limited and hastily resolves.
  • In patients with B-lymphocyte dysfunction, skeletal muscles can become chronically infected, manifested by a dermatomyositislike syndrome. Although other enteroviruses can be the cause, EV infection is most common.
  • EV-9 is associated with both acute and subacute arthritis.
• Pleurodynia (ie, Bornholm disease)
  • First described more than 2 centuries ago, pleurodynia is characterized by fever and spasmodic pain in the chest wall or upper abdomen. The hallmark of pleurodynia is its paroxysmal nature.
  • Spasmodic periods persist from a few minutes to half an hour or longer. Pain can be severe, and patients often appear pale and diaphoretic, sometimes leading physicians treating older adults to consider the possibility of a myocardial infarction. Patients present with shallow, frequent respirations that usually suggest pleural inflammation or pneumonia. Physical examination rarely reveals pleural friction rubs; pleural effusions occur in fewer than 10% of patients. Pain usually is more severe at presentation and gradually wanes over 4-6 days, although pain occasionally persists 3 weeks. Analgesics and restricted physical activity usually suffice to reduce pain. Abdominal wall involvement occurs almost exclusively in children and often mimics appendicitis or peritonitis.
  • Pleurodynia can occur in epidemics involving adults and children, or in sporadic form. EV-1 and EV-6 are associated with epidemics of pleurodynia, and almost all other EV types have been linked to sporadic cases.
• Myopericarditis
  • EV's tropism for the heart is well established. Group B coxsackieviruses 2 and 5 traditionally have been linked to acute myopericarditis; however, many other enterovirus types, including EV, have been related to acute heart disease. Although enterovirus-induced myocarditis occurs in all age groups, the highest risk is among physically active adolescents and young adults.
  • Myopericarditis is clinically indistinguishable from diseases caused by other viruses (eg, adenoviruses, influenza A, mumps) that can infect the myocardium. Approximately 65% of patients report an upper respiratory infection preceding manifestations of substernal chest pain, fever, dyspnea, and exertion intolerance. Physical examination reveals a pericardial friction rub in as many as 80% of these patients and a gallop rhythm in 20%.
  • Electrocardiography (ECG) invariably reveals abnormal findings; ECG also can reveal acute ventricular dilatation and diminished ventricular ejection fraction. Cardiac enzyme serum levels are often high.
  • Although the acute course of myopericarditis can be complicated by arrhythmias and congestive heart failure (CHF), most patients recover without major sequelae. About 5% of cases are fatal. Approximately 10-30% of cases continue to show ECG abnormalities; about the same percentage of patients present with recurrent CHF that indicates permanent myocardial damage. Most affected patients need supportive care.
  • Corticosteroid use is controversial for cases of acute myocarditis; experts disagree about the benefits and potential adverse effects of systemic use. Some have reported benefits from administering high-dose IVIG, but this therapy remains far from the standard of care.
• Neonatal infections
  • Neonates during their first 2 weeks of life are particularly susceptible to potentially lethal diseases caused by an EV infection. Vertical transmission from an infected mother or, more rarely, a nosocomial source is the most likely mechanism for acquiring infection.
  • Passive acquisition of immunoglobulin G (IgG) antibodies from the mother appears to determine the outcome of a neonatal infection more than any other factor. The critical issue is the amount of time between maternal infection and the delivery.
  • Neonates who are infected present with a sepsislike syndrome, with fever, irritability, lethargy, respiratory distress, and an exanthem. Many patients show radiographic evidence of pulmonary involvement, and CSF analysis provides evidence of meningitis. Major systemic manifestations can develop as the disease progresses, such as hepatic necrosis, myocarditis, and disseminated intravascular coagulation. CNS disease may progress to encephalitic characteristics with seizures and focal abnormalities. Because clinical features can imitate neonatal sepsis by bacterial agents and either disseminated or localized herpes simplex infection, patients are often treated for both possibilities.
  • EV-11 specifically has been linked to a clinical syndrome of disseminated sepsis in which the dominant feature is neonatal hepatitis, accompanied by extensive necrosis of the liver and overwhelming hepatic failure. Other serotypes able to cause neonatal liver disease include EV serotypes 6, 7, 9, 14, 17, 19, and 21. In addition, EV-6, EV-9, and EV-11 have been linked to a severe form of perinatal pneumonitis with a high mortality rate. Incidence of infant death due to perinatal EV infection is unknown, although some studies report high numbers. Mortality usually results from either overwhelming liver failure or myocarditis rather than CNS involvement.
• Other infections
  • EV-4 and EV-11 have been reported as sporadic causes of mild cases of croup.
  • EVs have sporadic associations with bronchitis and bronchiolitis.
  • Pneumonia in children has been associated with infections with EV serotypes 6, 7, 9, 11, 12, 19, 20, and 30.
  • Conjunctivitis, whether alone or in conjunction with other symptoms, has been reported with EV serotypes 1, 6, 9, 20, and 30.
  • Several reports link echovirus and enterovirus infection to a risk of developing type 1 diabetes.

Causes

Overcrowded conditions and poor hygiene easily explain the high prevalence of EV infections among lower socioeconomic groups.

• EV is transmitted person-to-person; the fecal-oral route is the predominant mode, and transmission sometimes occurs via respiration of oral secretions.
• Indirect transmission occurs through numerous routes, including contaminated water, food, and fomites. Contaminated swimming and wading pools can transmit the virus. Well-documented reports detail transmission via the contaminated hands of hospital personnel.
• EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.

Differential Diagnoses

Neonatal Sepsis

Other Problems to Be Considered

Bacterial sepsis
Bacterial meningitis
Neonatal herpes simplex infection
Herpes simplex virus encephalitis
Arbovirus encephalitis
Fever without localizing signs
Viral exanthems
Pharyngoconjunctival fever

Workup

Laboratory Studies

Until recently, the criterion standard laboratory procedure to diagnose echovirus (EV) and other enterovirus infections was to isolate the virus in cell culture. An etiologic diagnosis is confirmed when virus is isolated from blood, CSF, tissue, or pericardial fluid. EV can also be isolated from stool or oropharynx, although these findings are less indicative of disease because asymptomatic shedding from these sites can occur for several weeks after acute infection.

• Enteroviruses grow rapidly in cell culture, yet viral recovery occurs too slowly to provide data for decisions about treatment. Virus detection in cell culture typically takes 3-8 days, requires multiple cell lines for optimal recovery, is labor intensive and costly, and is not readily available in all clinical facilities. Antiviral therapy for enterovirus requires a faster and more efficient mechanism for diagnosis.
• Enterovirus polymerase chain reaction (EV-PCR), based on amplification of conserved genetic sequences, has been thoroughly studied and is superior to viral culture for revealing many enteroviral infections, particularly enteroviral meningitis.^5,6,7
  • EV-PCR can be used in samples other than CSF, although experience is not as extensive. EV-PCR has been successfully used in urine and serum to document neonatal infection and on throat swabs to document common outpatient illnesses.
  • Quality control from laboratory to laboratory is necessary because no commercial kit is available. Because of its extreme sensitivity, EV-PCR is subject to false-positive results from contamination within the laboratory. The greatest benefit of EV-PCR is that the test can provide results in 5-24 hours, which can expedite patient management decisions (eg, decrease length of hospitalization, antibiotic use, overall costs).
• Serologic tests for enteroviral infection diagnosis have limited value because they are slow, require acute and convalescent titers, and are not type-specific.

Treatment

Medical Care

No antiviral therapy has been available except IVIG therapy, which reportedly has some success in patients who are immunocompromised and have persistent enterovirus infections. The role of IVIG therapy for acute infections is unproven. A study evaluating its use in enteroviral infection in neonates failed to demonstrate a clear benefit. Another study evaluating the use of IVIG in 21 patients with myocarditis showed improved left ventricular function and survival when compared with 25 control patients. However, additional studies are needed.
Corticosteroid use to treat viral myopericarditis remains controversial at best. Several antiviral agents have in vitro activity against a broad range of enterovirus types, and several clinical trials have been conducted on their use.

• The first of these agents to be studied was pleconaril, a drug that interferes with the binding of enterovirus to the cell membrane and the uncoating of virions by attaching to the virus protein capsid.^8,9 Several clinical trials have demonstrated a benefit in children and adults with enterovirus meningitis.¹⁰ Pleconaril apparently may be on the verge of becoming readily available for clinical use as a new therapy option for echovirus (EV) and other enteroviral infections.
  • Pleconaril at concentrations of 0.1 mg/mL has activity against more than 90% of the most common circulating enteroviruses. The drug has good bioavailability and a prolonged half-life, allowing oral administration 3 times a day. Adequate levels can be achieved in serum and CSF.
  • Pleconaril has been studied in enteroviral meningitis, in respiratory tract infections, and in a limited number of patients who are immunocompromised and have viral myocarditis.
  • Phase III clinical trials are underway, and initial results are promising. In the first placebo-controlled double-blind study, 221 children (aged 4-14 years) with signs and symptoms of viral meningitis, most confirmed as enterovirus with EV-PCR, received 2.5 or 5 mg/kg of pleconaril or placebo 3 times a day for 7 days.¹⁰ Initial findings showed a 38-50% improvement among treated patients when compared with patients receiving a placebo. Improvement was seen as early as 24 hours after therapy initiation. Similar results have been obtained in studies of adolescents and adults with enteroviral meningitis. Pleconaril is currently under investigation in a multicenter collaborative study of therapy for neonatal enteroviral sepsis sponsored by the National Institutes of Health.
  • Schering-Plough lists pleconaril nasal spray as having completed phase II trials for preventing asthma exacerbation and common cold symptoms in asthmatic patients exposed to picornavirus.⁹
  • As of spring 2008, pleconaril is not approved by the US Food and Drug Administration (FDA).

Follow-up

Further Outpatient Care

• The specific type of infection caused by echovirus (EV) should dictate follow-up care.

Prognosis

• Neonates with disseminated encephalitis have a poor prognosis and many die. Children and older patients have a better prognosis, but the disease is occasionally fatal.
• Acute myopericarditis is fatal in approximately 5% of cases; most patients recover without major sequelae.
• The short-term prognosis for children with EV and enteroviral meningitis early in life appears to be good. The long-term prognosis for similarly affected children is controversial in regard to cognitive, developmental, and language abnormalities. Some recent prospective reports have indicated virtually no measurable long-term effects, even among patients with neurologic findings during their illness.
• The prognosis is generally poor for patients with chronic meningoencephalitis who have coxsackievirus or EV infections and acquired or congenital B-lymphocyte function defects.

Chlorhexidine Wipes Fail to Prevent Newborn Deaths and Sepsis

Nancy Fowler Larson

June 3, 2010 — Wiping vaginal areas before birth and swabbing newborns with chlorhexidine, an antiseptic solution, do not prevent sepsis (bacterial infection in the blood or tissues) or reduce the mortality rate of mothers or children, according to a study published in the June issue of Obstetrics & Gynecology.
In developed nations, where group B streptococci are most often the trigger for sepsis, antibiotics are showing their effectiveness, but in underdeveloped countries, where sepsis is a chief reason for neonatal death, the cause is more likely to be gram-negative bacteria (Klebsiella pneumonia and Escherichia coli), which may be transmitted during labor from the mother's genital tract to the fetus. No method of prevention has been proven, but antiseptic solutions have held promise.
"It has been proposed that peripartal infection of the fetus and mother may be prevented by intrapartum vaginal and neonatal wipes with an antiseptic solution," write Sarah Saleem, MBBS, from Aga Khan University, Karachi, Pakistan, and colleagues. "One such antiseptic solution is chlorhexidine, which has a wide range of effectiveness against aerobic and anaerobic gram-negative and gram-positive organisms."
The efficacy of chlorhexidine was suggested by a pilot study. Because subsequent research was plagued by methodological weaknesses, the researchers launched their randomized trial to determine the effect of chlorhexidine wipes on mortality of the unborn and newborns and on the morbidity caused by sepsis.
The investigators conducted a study of 5008 women from June 2005 through May 2008 in 3 Karachi hospitals that serve the poor. During this period, 2205 laboring women and their newborns were wiped with chlorhexidine and 2503 were wiped with a saline solution. A field team examined the mothers and infants at home at 7 days and 28 days. The primary outcome was infant death at 7 days or before or the presence of sepsis in living newborns.
There were few distinctions between groups regarding factors including the mother's age, number of previous births, gestational age, type of delivery, birth weight, sex, or Apgar score.
Maternal results revealed no important disparities between groups other than less frequent hospitalizations at 7 days for those who received chlorhexidine. Data on 1596 of the infants (32%) produced the following findings.

• There was little difference between groups regarding primary outcome (3.1% for the chlorhexidine group vs 3.4% for the control group; relative risk [RR], 0.91; 95% confidence interval [CI], 0.67 - 1.24; P = .57).
• No significant differences were found in the composite rate of neonatal sepsis or mortality at 28 days (3.8% vs 3.9%; RR, 0.96; 95% CI, 0.73 - 1.27; P = .79).
• On day 7, a lower rate of infant skin infection was found in the chlorhexidine group (3.3% vs 8.2%; P < .001).

"Using maternal chlorhexidine vaginal wipes during labor and neonatal chlorhexidine wipes does not reduce maternal and perinatal mortality or neonatal sepsis," the authors write. "The finding of reduced superficial skin infections on day 7 without change in sepsis or mortality suggests that this difference, although statistically significant, may not be of major importance."
There were no stated limitations to the study. The investigators encourage further research to diminish the widespread infections in developing countries.
"Despite the failure of chlorhexidine maternal and vaginal wipes to reduce sepsis, infection remains a major cause of neonatal morbidity and mortality in many developing-country settings," the authors write. "Thus, it is important to develop strategies that reduce or prevent newborn bacterial colonization and strategies that reduce death once infection occurs."
The National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research, the Bill and Melinda Gates Foundation, and Aga Khan University supported the study. A complete list of disclosed relevant financial relationships can be found in the article.

Cutting Intake of Sugar-Sweetened Drinks Lowers BP in Observational Study

Steve Stiles

 

May 26, 2010 (Dallas, Texas) — Cutting back on consumption of beverages that contain added sugar can lower blood pressure, but not only because it may reduce body weight, according to a prospective cohort study that also found no influence on BP from caffeine or consumption of diet soft drinks [1]. The analysis also suggested that change in overall intake of sugar, whether added to or naturally occurring in food and drink, had an effect on BP.
The study found--in its population of >800 adults participating in a hypertension trial of dietary and behavioral interventions--that drinking one less sugar-sweetened beverage a day was independently associated with declines of about 1.2 mm Hg and 1.1 mm Hg in systolic and diastolic BP, respectively, over 18 months. The relationships remained significant after researchers further controlled for weight change.
"Our study is observational in nature, but our data show that if you reduce sugary drink consumption, you will reduce blood pressure," lead author Dr Liwei Chen (Louisiana State University Health Science Center, New Orleans) told heartwire . The analysis was published online May 24, 2010 in Circulation.
The findings, she said, are consistent with studies using different animal models that show increased sugar intake can induce hypertension, even after controlling for weight. They also complement other observational studies suggesting links between dietary added sugar, including in soft drinks, and hypertension, dyslipidemia, and the metabolic syndrome, as heartwire has reported, but conflict with some of their data suggesting that the link between soft drinks and blood pressure extends to artificially sweetened soft drinks.
In the current study, a third of participants cut their consumption by 1.3 servings per day over 18 months, and systolic BP dropped 1.5 mm Hg more than it did in participants who didn't change their intake of sugar-sweetened beverages, Chen et al write. So intake reduced to at least that degree "should be achievable and could be beneficial."
In the current analysis, which included 810 participants in the randomized, multicenter PREMIER trial with prehypertension or stage 1 hypertension, daily intake of calories, different nutrients, and beverages (derived from the average of two 24-hour dietary recalls) was determined at baseline, six months, and 18 months.
Sugar-sweetened beverages, defined as any drinks with added sucrose or high-fructose corn syrup, included "soft drinks, fruit drinks, lemonade, fruit punch, and other sweetened beverages but excluded diet drinks. Diet beverages were defined as carbonated or noncarbonated drinks that were sweetened with [noncaloric] artificial sweeteners."
After a variety of potential influences on blood pressure, including body-mass index but not body weight, were controlled for, changes in sweetened beverage intake over 18 months were significantly related to changes in systolic and diastolic BP (p<0.001 for both). Adding weight change to the covariates attenuated both the effect of such intake on BP and its significance, although p values remained <0.05, "suggesting that reducing sugar-sweetened beverage intake has a BP-lowering effect that is independent of weight loss."
Relationship Between Blood Pressure Changes and Changes in Intake of One Serving (12 Ounces) of Sugar-Sweetened Beverage After 18 Months in PREMIER

Change in BP (mm Hg) per 1-serving difference	Model 1a	Model 2b
Systolic	1.76 (p<0.001)	0.70 (p=0.01)
Diastolic	1.08 (p<0.001)	0.38 (p=0.04)

a. Adjusted for sex, race, family history of hypertension, PREMIER treatment group, PREMIER site, age, alcohol intake, body-mass index, baseline sugar-sweetened beverage intake, baseline fitness, change in fitness, baseline physical activity, change in physical activity, baseline urinary sodium excretion, change in urinary sodium excretion, and adherence to DASH diet
b. Further adjusted for change in body weight
In the non–weight-adjusted model, systolic and diastolic pressures, respectively, changed 0.30 mm Hg (p<0.001) and 0.24 mm Hg (p<0.001), for every 10-g/day difference in total consumption of sugars from all food and beverages. The BP changes over 18 months were still significant when weight change was added to the model, at 0.17 mm Hg (p=0.003) and 0.15 mm Hg (p<0.001). Intake of caffeine or artificially sweetened drinks showed no significant relationships with blood pressure in either model.
"Our study has important public-health implications," observe Chen et al. "For example, it has been estimated that a 3-mm-Hg reduction in systolic BP should reduce stroke mortality by 8% and coronary heart disease mortality by 5%. Such reductions in systolic BP would be anticipated by reducing sugar-sweetened beverage consumption by an average of two servings per day."
PREMIER was funded by the National, Heart, Lung, and Blood Institute; the current analysis was partially supported by grants from Louisiana State University and Johns Hopkins University (Baltimore, MD). None of the coauthors had disclosures.

Global Headway in Maternal Mortality

Peter Kovacs, MD, PhD

Authors and Disclosures

Posted: 05/27/2010

 

Maternal Mortality for 181 Countries, 1980-2008: A Systematic Analysis of Progress Towards Millennium Development Goal 5

Hogan MC, Foreman KJ, Naghavi M, et al
Lancet. 2010;375:1609-1623

Background

During pregnancy, women are at increased risk for certain medical complications. The body undergoes numerous physiologic adaptations to be able to care for the growing pregnancy. The cardiovascular, urinary, respiratory, immune, and other systems all undergo these adaptive changes. Because pregnant women are typically young and healthy, these changes occur easily. The case is different for women who have preexisting medical conditions. Even when these conditions are well-controlled before conception, the physiologic changes may lead to abnormal function and place the future mother at risk. In addition, women respond differently to medical problems during pregnancy. For example, viral infections tend to be more severe, as was clearly seen with the recent H1N1 outbreak.
With adequate preconception care, medical conditions that require careful management before and during pregnancy can be identified, and the risks associated with pregnancy can be minimized.
Data on maternal mortality help healthcare authorities systematically identify medical problems that require special attention in pregnancy. These data also help clinicians identify the main causes for maternal mortality, and allow them to attack these problems actively before women become pregnant. In addition, international organizations can use such data to find intervention programs that must be coordinated at an international level (eg, research, education, screening). This article analyzed maternal mortality data for a 28-year period in 181 countries.

Study Summary

Maternal mortality is defined as death of the mother during pregnancy, during delivery, or within 42 days postpartum. The maternal mortality ratio (MMR) is the number of maternal deaths for every 100,000 births. For this analysis, data were collected from several sources: vital registration systems, sibling histories, censuses, and published national and subnational data. International Classification of Diseases codes were used for data identification.
The number of maternal deaths worldwide was down to 342,900 (uncertainty range: 302,100-394,300) from 526,300 (uncertainty range: 446,400-629,600) between 1980 and 2008. The annual rate of decline in the MMR was 1.85% between 1980 and 1990, and then slowed down to 1.4% after 1990. The slowing of the decline in MMR is believed to be a consequence of the HIV epidemic in the early 1990s. The MMR was reduced to 251 (uncertainty range: 221-289) from 320 (uncertainty range: 272-388) for the same time period. Most maternal deaths were seen in sub-Saharan Africa (52% of all maternal deaths in 2008). The MMR was less than 20/100,000 in 5 regions: Australasia, western Europe, central Europe, high-income North America, and high-income Asia-Pacific. The MMR was more than 200/100,000 in the following regions: south Asia, Caribbean, Oceania, and sub-Saharan Africa (central/east/south/west). The region with the highest MMR was west sub-Saharan Africa (629), and the country with the highest MMR was Afghanistan (1575). MMR increased in sub-Saharan Africa in the 1990s, mainly because of HIV infection.
Of the 181 countries analyzed, 21 countries with the highest maternal mortality were responsible for almost 80% of the maternal deaths and 60% of all live births. In the United States, Canada, Norway, and Afghanistan, MMR increased slightly.

Viewpoint

Maternal mortality is defined as the death of the mother during pregnancy, delivery, or up until 42 days postpartum. Reporting and coding differences may partially explain the findings of this study, especially when the numbers from developed countries (United States, Canada, and Norway) are considered, but other potential explanations also exist for the findings of this study.
The investigators noted that the total fertility rate is positively associated with maternal mortality, whereas gross domestic product (GDP per head) negatively influences the MMR. The overall health status of the population continuously changes as well. Obesity is becoming more prevalent and is known to be associated with adverse pregnancy outcomes.^[1] Women who delay childbearing and pregnancy (especially over the age of 40) are at higher risk for morbidity (hypertensive complications, gestational diabetes, operative delivery) and death. In developed countries, infertility is a growing problem, and more and more patients use infertility services. In Europe, 1%-4% of live births are conceived through assisted reproductive technology (ART). The number of multiple gestations is higher after ART, and maternal risks are more common with multifetal gestations.^[2]
The quality of healthcare and access to healthcare in general correlate with a country's GDP. In countries where access to healthcare is limited, maternal morbidity and mortality are higher. In countries with well-functioning screening and vaccination programs, maternal mortality is less likely to be related to infections. In the 1990s, the decline in the MMR slowed down as a result of the rise in the number of HIV infections. In countries where access to antiretroviral drugs is limited, MMR rates remained high (eg, sub-Saharan Africa). The recent H1N1 epidemic highlighted the importance of effective vaccination programs.
The data presented in this article could be very useful for healthcare authorities by helping them identify the regions where the most improvement could be achieved with the introduction of patient and provider education programs, screening programs, drug distribution, and vaccination. It is reassuring to see that in most countries the figures are improving, but it is also obvious that there is room for further improvement. The biggest improvement can be expected in the developing countries. Managing pregnancy complications caused by infections, malnutrition, and lack of available medical care (both before and during pregnancy) could result in substantial improvement within a short period of time. On the other hand, in the developed world, it is going to be difficult to further improve the numbers. More emphasis must be put on preconception care, and patients must be informed about the adverse effects of factors such as delayed childbearing, obesity, and inappropriate nutrition. This certainly is a challenging task for health authorities in most countries.

Treating Obese Patients: The Importance of Improving Provider-Patient Interaction

Rebecca M. Puhl, PhD

Authors and Disclosures

Posted: 05/27/2010

Introduction

Two thirds of Americans are now overweight or obese, so healthcare providers frequently interact with patients who are struggling to lose weight. Indeed, obesity is an important clinical problem that cannot be ignored, and high quality healthcare is critical in efforts to improve health in this population. It is surprising, then, that instead of support and encouragement, obese patients are often treated with insensitivity and judgment, as evidenced by the following experiences related by obese individuals:
"I became very frustrated when a doctor disregarded what I was telling him because he had already made up his mind that obesity was at the root of all my problems."
"My family doctor had a habit of shrugging off my health concerns. The last time I went to him with a problem, he said, 'You just need to learn to push yourself away from the table.'"
"I asked a gynecologist for help with low libido. His response was, 'Lose weight so your husband is interested. That will solve your problem.' I changed doctors after that! And I've told everyone I know to stay away from him."
"I told my doctor that I needed help to lose weight, and he accused me of being a 'closet eater' and wasn't going to put me on anything until I learned to eat better. When I protested, he just laughed. This had a huge impact on me, and I changed doctors the next day.”
"Nurses in the doctors' waiting room stated aloud that if people in waiting room had any willpower that they wouldn't be there. I was very upset but at the time too shy to respond to it."
"My doctor said, 'You are cheating or you would have lost weight.'"

The Problem of Weight Bias

Unfortunately, experiences like these are common for obese patients.^[1,2] Research demonstrates that obese patients frequently feel stigmatized in healthcare settings. Overweight or obese patients are more likely to avoid routine preventive care, and when they do seek health services, they may receive compromised care. When obese patients feel stigmatized, they are vulnerable to depression, low self-esteem, anxiety, and suicide. They are less likely to feel motivated to adopt lifestyle changes and may engage in unhealthy eating patterns and avoid physical activity, which can exacerbate weight gain.^[3] Simply put, weight stigmatization jeopardizes patients' emotional and physical health.
Providers may unintentionally communicate overt or subtle forms of bias that can negatively affect patients' care and their future utilization of healthcare services. The problem of weight stigma is serious and pervasive, and providers should be aware of this issue in their clinical practice.

Eliminating Weight Bias

Providers can use a number of strategies to increase sensitivity and reduce weight bias in their interactions with patients.
Acknowledge attitudes about obesity. First, it's critical to identify personal attitudes and assumptions about body weight that might unintentionally lead to bias or stigma. Ask yourself the following questions to increase your self-awareness of potential personal biases:

• Do I make assumptions about a person's character, intelligence, health status, or lifestyle behaviors based only on body weight?
• Am I comfortable working with patients of all sizes?
• What kind of feedback do I give obese patients?
• Am I sensitive to the needs and concerns of obese patients?
• What are common stereotypes about obese people? Do I believe these to be true or false? What are my reasons for my beliefs?

After reflecting on these questions, look for examples of overweight individuals (eg, patients, family members, friends, coworkers, or even celebrities or athletes) who challenge weight-based stereotypes. Challenge yourself to question your personal assumptions about body weight.
Adopt sensitive language. Effective communication is the key to providing quality healthcare. This can be especially important with obese patients who may have experienced negative interactions with other providers. It is important to approach conversations about body weight and obesity in a sensitive manner.
It can be challenging to discuss health issues related to excess weight while also remaining sensitive to terminology and language that may offend patients. To facilitate positive patient-provider interactions, providers must recognize and use weight-related language with which the patient feels comfortable. For example, some research has examined specific terms that obese patients prefer (or dislike) for describing their body weight. Patients prefer words like "weight," "excess weight," or "body mass index" to "large size," "weight problem," or "unhealthy body weight."^[4] It's likely that personal preferences of patients will vary, so it can be helpful to ask them about preferred terms before discussing body weight issues.
Use effective communication strategies. Certain communication strategies can encourage a patient's motivation to engage in healthy lifestyle behaviors without being judgmental or biased. One particularly effective approach is motivational interviewing, which aims to enhance self-efficacy and personal control for behavior change. This approach uses an interactive, empathic listening style to increase motivation and confidence by specifically emphasizing the discrepancy between personal goals and current health behaviors.^[5]
The types of questions typically used for this approach are open-ended, nonjudgmental questions, such as:

• How ready do you feel to change your eating patterns and/or lifestyle behaviors?
• How is your current weight affecting your life right now?
• What kinds of things have you done in the past to change your eating?
• What strategies have worked for you in the past?
• On a scale from 1-10, how ready are you to make changes in your eating patterns?

These types of questions increase providers' understanding of patients' beliefs, concerns, and expectations; help patients feel understood; and facilitate patients' involvement in decisions that affect their health.
Provide bias-free care. Finally, improving quality of care for obese patients requires implementing strategies to promote bias-free treatment. This means recognition that obesity is a product of many factors -- a complex interaction of genetic, biological, societal, environmental, and psychological contributors. Appreciation of the complex etiology of obesity can help providers avoid placing blame on patients for their obesity. Similarly, it is important for providers to explore all causes of the patient's presenting problems rather than assuming that body weight is the only target for intervention.
When establishing goals for treatment, it is also useful to emphasize the patient's behavioral changes rather than focusing only on the number on the scale. Setting specific, realistic, and measurable goals with respect to eating habits and physical activity levels increases the likelihood that patients will succeed in making healthy changes and communicates the importance of health rather than thinness. Finally, it can be helpful for both providers and patients to discuss the benefits of small weight losses, which can result in considerable improvements in health. Very few obese patients reach their "ideal" weight, but many can experience significant health gains with even a 5% or 10% reduction in their weight.

Conclusion

Healthcare settings should be safe havens where obese patients feel comfortable seeking support not only with weight management but also a broad range of wellness issues. Unfortunately, many patients experience instead shame, stigma, and prejudice. As providers, it is our duty to ensure that all patients are treated with dignity and respect and that their quality of care is not compromised by biased attitudes. By increasing awareness of personal weight-based attitudes and providing sensitive and compassionate care, providers can help create healthcare experiences that instill hope, rather than shame, in this vulnerable patient population.
For more information and free resources about weight bias and stigma, please visit the following website: http://www.yaleruddcenter.org/what_we_do.aspx?id=10

Cancer Immunotherapy CME

Fundamentals of Cancer Immunotherapy CME

Mary L. "Nora" Disis, MD

processing....

CME Information

Target Audience

This activity is intended for oncologists, hematologists, pathologists, dermatologists, and other healthcare professionals involved in the management of cancer with immune-based therapies.

Goal

The goal of this activity is to examine the potential for and current use of immune-based therapies for the treatment of cancer.

Authors and Disclosures

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Describe the different classes of immunotherapies and the mechanisms of their anticancer effects
2. Demonstrate appropriate strategies for prevention and management of adverse events associated with cancer immunotherapies
3. Evaluate the unique patterns of response that may be associated with cancer immunotherapies

 

Introduction

Treating cancer by harnessing a patient's immune system has several major advantages over other forms of cancer therapy (Table 1). For example, some cells of the immune system can respond to specific immunogenic proteins, or antigens, expressed by the tumor. This characteristic allows specificity of the immune response to cancer without excessive toxicity to normal tissues, as is seen with cytotoxic chemotherapy. Antigen-specific T lymphocytes, presumably the most important component of the immune system in mediating an antitumor response, have the capability of homing to any site of cancer even if disease deposits are located deep in tissues.^[1] Therefore, unlike other standard forms of cancer treatment, the immune response has the potential to eradicate cancer in any location. Cancer-specific T and B lymphocytes are cells that can directly induce tissue destruction and will continue to proliferate and function as long as there is antigen present to stimulate their activity. For this reason, once a robust immune response is elicited, no further immune-based treatments would be necessary. Finally, a key characteristic of an effective immune response is the generation of immunologic memory, which is the persistence of an antigen-specific immune response over many years. If the cancer antigen is sensed again, even decades after the initial diagnosis of disease, immune cells will rapidly respond, proliferate, and destroy antigen-expressing cancer cells before those cells have the chance to become re-established.

Unfortunately, the development of actual immune-based therapies for the treatment of cancer has been challenging. In large part, the challenges have been due to the nature of the immunogenic proteins that are expressed by human tumors. Over the last decade, a host of human tumor antigens have been identified as potential therapeutic targets. Some antigens expressed in tumors are viruses -- hepatitis B virus (HBV) in hepatocellular carcinoma, Epstein-Barr virus (EBV) in lymphomas and nasopharyngeal carcinomas, and human papillomavirus (HPV) in cervical cancer are just a few examples -- but most immunogenic cancer-associated proteins are normal cellular proteins (self proteins) that have become qualitatively or quantitatively altered in the malignant state as compared with their expression in normal tissues. Clinical responses to immunotherapies targeting either viral or self proteins have been reported.^[2] Immunologic targeting of a cancer-related self protein is hampered by the multiple mechanisms our bodies have of preventing autoimmunity. The inflammatory response that develops when cancer grows elicits immune system cells that are likely to turn off a destructive cancer-specific immune response because the antigens being recognized are perceived as "self." Certain types of macrophage, termed M2, will secrete cytokines that prevent T-cell proliferation.^[3] Immature myeloid cells, myeloid-derived suppressive cells, are also present in the tumor bed and can inhibit the generation of a clinically productive immune response by preventing antigen-specific T cells from functioning correctly.^[4] T cells themselves can differentiate into regulatory cells when they sense self antigens and prevent further tumor recognition via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, which are immune-suppressant cytokines.^[5] These are just a few of the natural defense mechanisms in place for preventing the development of autoimmune disease; unfortunately, these same mechanisms limit the tumor-specific immune response. Effective cancer immunotherapy must generate a destructive immune response as well as control tolerizing mechanisms that are in place to limit self-specific immunity.
Despite the challenges, there are several immune-based therapies that are routinely used in the treatment of cancer patients. Cancer immunotherapy is generally classified as being "active" or "passive" (Table 2). Active immunotherapy is a treatment modality that functions by stimulating the patient's own immune system to generate the cells needed to impart an antitumor effect. An example of an active immunotherapy would be a vaccine. The vaccine is administered to stimulate T or B lymphocytes to recognize and destroy the cancer. The use of nonspecific immunomodulators such as bacillus Calmette-Guerin (BCG) would also be considered active immunotherapy. After administration of BCG, it is assumed that cells of the innate immune system, present in the patients, would respond and cause inflammation that could result in the eradication of superficial bladder cancer. In the case of active immunotherapy, patients must have immune systems capable of competently responding to stimulation. For this reason, in general, active immunotherapy is not effective in patients with advanced-stage refractory disease who may have a depressed number of immune system cells able to adequately function. Passive immunotherapy provides the immune response to the patients. Monoclonal antibody therapy is considered a passive immunotherapy. Rather than stimulating a patient's own antibody response, the infusion of monoclonal antibodies provides the antigen-specific antibodies to the patient. Similarly, rather than stimulating a patient's own T cells via vaccination, adoptive T-cell therapy infuses high numbers of antigen-specific T cells into patients, thus providing immediate robust immunity to a specific target. Because patients do not have to generate their own endogenous immune response, passive immunotherapy is often used in the treatment of patients with well established and even refractory cancers. An example of adoptive T-cell therapy would be the use of donor lymphocyte infusions in the treatment of chronic myeloid leukemia (CML) that has relapsed after allogeneic hematopoietic stem cell transplant (HSCT).

The potential mechanisms of action of many cancer immunotherapies are multifactorial and often not fully understood because the immune system is a complex organization of numerous components, pathways, and interdependent interactions. The cell types involved in mediating tumor-specific immunity will define the clinical efficacy as well as the toxicities associated with targeted immune-based treatments.

Amphetamines in the management of children's hyperkinesis (hyperactivity)

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From V. SINGH , G. M. LING, 1979

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Amphetamines in the management of children's hyperkinesis

V. SINGH Children's Hospital, Vancouver, B.C., Canada
G. M. LING Director, UN Division of Narcotic Drugs, Vienna

Introduction

Hyperkinesis or hyperactivity has been commonly used to refer to a state of altered behaviour in children (Safer and Allen, 1976; Kolata, 1978). The most prominent feature of hyperactivity is the inability to maintain attention. Although hyperactivity as a clinical entity is widely recognized, the prevalence of this disorder varies from 1.0 per cent in some countries to 40.0 per cent in others. In addition, the topic of hyperactivity appears to be very controversial because of conflicting descriptions of its definition, diagnosis and treatment.
The major features of hyperactivity are:

1. Inattentiveness-which refers to a short attention span and inability to concentrate on a problem for any length of time either at play or in school;
   
2. Over activity-constant repetition of an activity which is under no voluntary control, and which surpasses normal engagement in the same tasks;
   
3. Learning impediment-usually associated with poor school work, clumsiness and lack of communication in the classroom;
   
4. Uncontrolled impulsivity-the child is described as being tense, chronically unhappy and acts on the spur of the moment without thinking.
   

This list clearly indicates that the term hyperactivity simply describes the characteristic behavioural pattern of an individual's condition at one point in time. This results in a heterogeneous group of children being classified hyperactive on the basis of a variety of tasks that they perform or the behavioural profiles that they exhibit at school, play or home. Often, the relevant subgroups can be identified, one of which is really pronounced. This type of classification poses the very real problem of defining the term hyperactivity precisely as well as evaluating the disordered behaviour by means of appropriate diagnostic measures.
Other basic problems also are inherent in the terminology of hyperactivity. For example, in diagnoses, the terms "hyperactivity" and "minimal brain damage" (MBD) are commonly used to refer to the same syndrome. However the two terms are not identical in their meaning. The hyperactive children do not always have a learning or perceptual disability which is commonly associated with the MBD syndrome. On the other hand, MBD children are not always hyperactive or excessively restless. Furthermore, there is no evidence of anatomical brain damage in hyperkinetic children, although a minimal dysfunction might occur during the development of the brain resulting in developmental hyperactivity. This term is preferred by some investigators to describe an excessively overactive child.

Basis of hyperkinesis

In the historical context, there has been a prevailing debate about hyperactivity being a "reality" or a "myth". The answer to this question resides entirely in the definition of clinical diagnostic practice. Family physicians have observed the occurrence of a set of symbols identifying altered behaviour in children, and consequently described this behavioural pattern as the "hyperactive syndrome". In recent years, however, it has become apparent that the syndrome of hyperactivity is a medico-social problem which may involve neurological components as well as social and environmental factors. Knowledge of brain function derived over the last decade suggests that behavioural profiles can be interpreted at the level of specialized biochemistry of nerve cells, with respect to discrete brain areas.
Many theories have been developed to unravel a possible neurochemical abnormality underlying hyperactivity or hyperkinesis. One of these suggests that this syndrome derives from impaired inhibitory mechanisms in the central nervous system. Since a large number of inhibitory neural pathways in the brain utilize norepinephrine, dopamine and serotonin as neurotransmitters, a "monoaminergic theory" has been developed to explain hyperactivity (see Silbergeld, 1977). This theory implies an under functioning of catecholaminergic neurons in CNS. Alternative proposals have also been suggested which include age-related immaturity in the functional development of the brain, infectious diseases, brain injury, lead poisoning and the associated effects of adverse psychosocial experiences.
For example, prolonged institutionalization during early childhood may generate difficulties in a child to form meaningful relationships which may lead to certain temperamental and cognitive abnormalities, including hyperactivity, inability to concentrate and difficulties in abstraction. Similarly, children from disorganized families may become preoccupied with the tasks of searching for reliable and satisfying contact with people, avoiding pain and compensating for deficiencies in their growth; under stress, they characteristically respond with a motor discharge of tension, and show low frustration tolerance, impulsivity and unreliable self-control. These psychosocial experiences may interact with physiological predisposition to aggravate the manifestations of the hyperkinetic syndrome.

Stimulant medication and hyperkinesis

During the past two decades, stimulant drugs have been the most frequent treatment approach for the clinical management of the child with hyperactivity. Recent studies suggest that approximately 2 per cent of all elementary school children who suffer from the hyperactive syndrome receive psycho-stimulant medication. In this context, dextroamphetamine sulfate (Dexedrine) and methylphenidate hydrochloride (Ritalin) are frequently used.
The antianxiety and antipsychotic compounds are recommended as alternative therapies in patients who fail to respond to methylphenidate or d-amphetamine. The antidepressant, imipramine and the anticonvulsant, diphenylhydantoin also are beneficial, while sedative drugs such as barbiturates are contraindicated because they tend to exacerbate hyperactivity. In a number of controlled studies it has been shown that on the average more than 50 per cent of hyperkinetic children who had been given amphetamines showed improvement while only 26 per cent did not change or were exacerbated by the drug. Similar improvement rates are seen in children to whom methylphenidate or magnesium pemoline was administered, (Steinberg, 1971).

METHYLPHENIDATE

Methylphenidate, a central stimulant, has been shown to decrease consistently hyperkinesis, aggressive behaviour and impulsivity. Methylphenidate has also been reported to increase attention span and learning performance and is effective in the management of trans-situationally hyperactive children. It is generally believed that methylphenidate stimulates the cerebral cortex, thereby enhancing the function of consciousness. It also exerts a stabilizing influence on structures such as the limbic system which play a role in determining the subject's emotional reactivity. Animal studies have shown that methylphenidate produces amphetamine-like stereotyped behaviour which is mediated by striatal dopaminergic mechanism, and it has been proposed that this CNS stimulant produces its pharmacological effects by enhancing central dopaminergic effects (Garfinkel et al., 1975). In patients who develop tolerance to the effects of methylphenidate, or in those whose parents and teachers report no improvement and for whom neuropsychological tests are unchanged, an alternative medication such as d-amphetamine or imipramine is reported to produce beneficial results.

DEXTROAMPHETAMINE

In a study Arnold et al. (1976) demonstrated that levoamphetamine and dextroamphetamine were equi-potent in treating MBD children particularly with reference to decreasing hyperactivity and aggressiveness. These authors further reported that levoamphetamine showed a decreased tendency to produce the blunt effect and the "amphetamine look" than dextroamphetamine. Levoamphetamine produces less euphoria than dextroamphetamine and reports indicate that the former compound may be a logical choice where there is concern about danger of addiction and possible abuse of the child's stimulant supply. It has been suggested earlier that the action and effects of the hyperkinetic syndrome may be produced via dopaminergic mediation. This view gains additional support from studies in which two optical insomers (dextro and levo) of amphetamines were found equipotent in inhibiting dopamine uptake; however, dextroamphetamine was ten times as potent as levoamphetamine in inhibiting the uptake of neropinephrine in brains of rats pretreated with reserpine (Coyle and Snyder, 1969).

MAGNESIUM PEMOLINE

Magnesium pemoline is another CNS stimulant which has shown promise in treatment of hyperactive children with behavioural disorders. This compound was found to be clinically and statistically superior to placebo on the various measures, which included efficacy in improving learning performance, increasing attention span and decreasing impulsivity (Page et al., 1974). In contrast to amphetamine and methylphenidate, pemoline has fewer autonomic effects and longer duration of action and therefore can be given in a single dose. Pemoline has also been shown to potentiate central catecholamine effects and has been postulated to increase attention span and memory acquisition (Plotnikoff, 1971). While the exact mode of pharmacodynamic action in man is unknown, pemoline has been reported to increase the synthesis of dopamine in rat brain (Tagliamonte et al., 1971).
This CNS stimulant elicits no effect on the synthesis rates of brain norepinephine and serotonin.

TRICYCLIC ANTIDEPRESSANTS

Imipramine and amitriptyline have been used in the treatment of hyperkinesis and have been reported to possess an effectiveness similar to that seen with amphetamines and methylphenidate. A marked improvement in learning skills, as well as progress in alertness and attention span has been noticed in such children after treatment with imipramine. This tricyclic antidepressant is sometimes used as alternative medication in the treatment of the hyperactive child, but it also tends to increase systolic and diastolic blood pressure and pulse rate. (Greenberg and Yellin, 1975).

Diet in the management of hyperkinesis

There is some evidence suggesting that hyperactive behaviour is associated with food allergies. Benzamin Feingold (1976) reported that 30 to 50 per cent of children diagnosed as hyperkinetic experienced a dramatic response to a diet free of artificial food colours and artificial food flavours. However, these observations of Feingold were not substantiated by the subsequent studies of Harley and Associates (1977), suggesting that additional research should be conducted in this area.

Stimulant drug side effects

A review of clinical data indicates that the most prominent side effects associated with the long-term use of CNS stimulants are insomnia or sleep disturbances, and decreased appetite. The next most frequent appear to be weight loss, suppressed growth rate, irritability and abdominal pain. Other side effects of lesser frequency are headaches, drowsiness, dizziness, euphoria, nightmares, tremor, dry mouth, dazed appearance, nervous tics and anxiety. Many investigators found these side effects to be temporary and easily modified by adjusting dosages downwards (Bradley, 1950; Werry and Sprague, 1974). Short-term effects, noticeable during the first or second week of treatment may include: headaches, moodiness, stomach aches, temporary insomnia, reduced appetite and some phases of depressive irritability. Long-term effects which are reported to be rare may result from the drug therapy itself. These include development of psychological dependence, altered sleep pattern and a certain degree of suppression of growth rate.

Problems of long-term drug treatment

Once stimulant therapy appears to be beneficial to a hyperactive child, the long-term or continued treatment becomes an important and interesting issue from the point of view of the school as well as the parents. The maintenance of effective treatment, the detection of unexpected changes in behaviour and adequate medical follow-up are some factors to be taken into consideration. Depending upon the course dosage and outcome of treatment, drug dependence may develop. Therefore it is important for parents and school teachers and physicians to observe the behavioural profiles of stimulant-treated children continuously over a period of several years, in order to observe the degree to which dependence may have occurred. Stimulants offer little or no benefit to hyperkinetic children over 12-13 years of age, and if such therapy is continued past this age, there is an increased risk for dependence to develop.

Present status of stimulant therapy

Subjective observations indicate that teachers perceive hyperkinetic children as having improved "achievement" while treated with stimulant drugs (Schain and Reynard, 1975; Arnold et al., 1976). There is a short-term positive effect as regards classroom manageability in terms of increased attentiveness and concentration. However, while this is positive evidence in favour of hyperactivity treatment with stimulant drugs, the rationale behind this therapeutic approach has recently been brought under question (see Kolata, 1978), mainly because of the following inherent problems of definition, the diagnostic confusion about this syndrome and the stimulant treatment for it. For example,

1. By definition, hyperkinesis refers to a syndrome of altered behaviour in children. It is also believed that hyperkinesis is simply an emotional problem which overlaps with childhood depression (Miller, 1978).
   
2. Hyperkinetic children represent a very heterogeneous group of subjects in terms of their behavioural profiles.
   
3. The diagnostic measures, which are commonly employed, relate only to visual motor activity. Similarly the evaluation of successful stimulant treatment reflects changes only in visual-motor function. Since the hyperkinetic syndrome involves dysfunction of multiple parameters, possibly at the neurological level in brain, all of these should be taken into consideration during the course of diagnosis.
   
4. Stimulant treatment is not consistently successful in that there is a group of hyperactive children benefiting from it while another group derives no benefit.
   
5. There are several side-effects which occur especially after long-term therapy with stimulant drugs, e.g. increase in heart rate and blood pressure (Rapoport et al., 1974); alteration of sleep patterns and growth rate (Safer and Allen, 1973; Weiss et al., 1975).
   
6. Prolonged use of stimulant drugs has some adverse effects on academic skills (Weiss et al., 1975). More recently, objective analyses of hyperkinetic children have revealed no improvement of their academic performance (Barkley and Cunningham, 1978).
   
7. Until recently, there was no control study of a population of normal or non-hyperactive children treated solely with amphetamine. By including such a control study Rapoport et al., (1978) found no major improvement and the amphetamine response in normal and hyper kinetic children was similar, suggesting the lack of specificity of this therapy.
   

1. The "monoaminergic theory" of hyperkinesis implies the involvement of brain catecholamines. However, there is no actual data on the levels of catecholamines estimated in hyperactive children's serum, urine or tissue biopsies. Research is needed in this area.
   
2. Recently it has been shown that the continuous administration of amphetamine to laboratory animals (rats) for as long as 110 days induces a selective and severe neurotoxic effect on dopamine nerve-terminals in the caudate nucleus, the area of the brain which is intimately associated with motor functions (Ellison et al., 1978).
   

Prospects for research and concluding remarks

Although there are general problems in interpreting animal experiments to a clinical human setting, some recent studies with animal models offer good hope for the understanding of paradoxical responses to amphetamines (Silbergeld and Goldberg, 1974; Alpern and Greer, 1977). Likewise the work of Ellison et al. (1978) with rats has yielded new information regarding the effects of amphetamine administration which might occur with stimulant therapy. Furthermore, it can be anticipated that research experiments with laboratory animals may elucidate some of the conflicting issues surrounding the hyperkinetic syndrome. In this respect the following proposals merit attention:

1. Amphetamine actions on catecholamine systems should be thoroughly screened for regional specificity in the brain. This should lead to localization of neuroanatomical substrates for hypermotility elicited in animals by this drug.
   
2. Amphetamine-induced euphoric activity should be explored in relation to other neurotransmitter substances in CNS, e.g. amino acids (glutamate, GABA, aspartate, glycine and taurine) and neuropeptides (endorphins and substance P). It may be hypothesized that if amphetamine exerts its effects through central catecholaminergic pathways then other neural systems that are interacting with them might modulate or mediate the actions of this drug. Some recent work lends support to this suggestion. Pert and Sivit (1977) have found that endorphins, like catecholaminergic agonists, potentiate spontaneous motor activity in rats. Endorphins are opiate peptides and are distributed throughout the CNS and PNS, possibly with a neuromodulator function. Another set of data are derived by the use of a neurochemical kainic acid, a structural analogue of amino acids glutamate and a very potent CNS excitant. Fibiger and his colleagues (1978) have shown that intrastrial injections of kainic acid enhance amphetamine-induced stereotyped behaviour in rats. Such an effect would be very interesting since kainic acid is also known to cause degeneration of cholinergic and GABA neurons (McGeer et al., 1976), and to induce an "active gliosis" (Singh et al., 1978).
   
3. There may be a congenital basis for childhood hyperkinesis (see Kolata, 1978). If so, then virologic and immunologic assessment should be considered.
   
4. Frequently recommended alternatives to stimulant treatment for childhood hyperkinesis such as behaviour therapy, should be encouraged. Since hyperkinesis usually refers to the syndrome of disordered behaviour in children, the modification of behaviour towards normal is socially desirable. Under behaviour therapy, this goal is achieved either by changing a specific pattern of abnormal behaviour or by developing a missing pattern of behaviour. The common tools of this type of therapy are - desensitization to fear, increasing the capacity of self-control or motivation, and group reinforcement for improved social adjustments. In general, behavioural therapy helps in the improvement of school-directed problems, but harmonious and integrated commitment between family, school and child is mandatory. Although some uncertainty exists about the usefulness of behaviour therapy (Eisenberg, 1978), there is ample evidence which suggests that the management of the hyperkinetic syndrome by means of behaviour therapy can be an effective and viable alternative to stimulant therapy (Ayllon et al., 1975; O'Leary and Pelham, 1978).
   

Childhood hyperkinesis denotes a heterogeneous group of behaviour disorders. The etiology is unclear. The criteria used to diagnose this syndrome are limited and mainly describe the child's inability to manipulate visual-motor function. This diagnostic approach does not have a strong clinical foundation and presents difficulties in distinguishing closely the characteristics of hyperactive children from childhood depression usually connected with emotional problems. While hyperkinesis does not seem to be a disease, school personnel evidently perceive child's behaviour as abnormal in relation to classroom situations and academic skills.
Stimulant medication is the most commonly prescribed form of treatment for the hyperactive child. The benefits are inconsistent: no sound evidence exists for the reported paradoxical effect of these drugs, and it has not been consistently demonstrated that children treated solely with stimulants subsequently do better in school.
Also, there is no evidence of brain lesions in hyperkinetic children. The proposal of a monoaminergic theory to explain a neurochemical basis of hyperkinesis would imply the possibility of functional neurological pathology. In this regard, it is of interest that the actions and effects of stimulant drugs used in this connection are related to catecholaminegic mechanisms in the central nervous system. Future experiments with animal models might provide a way to the nature and causes of childhood hyperactivity.

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