Erythema Multiforme

Background

Erythema multiforme (EM) is an acute, self-limited, and sometimes recurring skin condition that is considered to be a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers.
 
Erythema multiforme may be present within a wide spectrum of severity. Erythema multiforme minor represents a localized eruption of the skin with minimal or no mucosal involvement. The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities (see the following image). Lesions remain in a fixed location for at least 7 days and then begin to heal. Lesions may also appear as arcuate lesions (see the second image below). Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus (EBV), and histoplasmosis. Because this condition may be related to a persistent antigenic stimulus, recurrence is the rule rather than the exception, with most affected individuals experiencing 1-2 recurrences per year.
 
Target lesion of erythema multiforme.
 
Raised atypical targets and arcuate lesions.  
 Raised atypical targets and arcuate lesions. Raised atypical targets and arcuate lesions.

Erythema multiforme major and Stevens-Johnson syndrome (SJS), however, are more severe, potentially life-threatening disorders (see the image below). Lesions of Steven-Johnson syndrome typically begin on the face and trunk. They are flat, atypical lesions, described as irregular purpuric macules with occasional blistering. Most patients also have extensive mucosal involvement. More than 50% of all cases are attributed to medications.

Note extensive sloughing of epidermis. 
Courtesy ofNote extensive sloughing of epidermis. Courtesy of David F. Butler, MD.
 Erythema multiforme vs SJS and TENS

Controversy exists in the literature with regard to the clinical definitions of erythema multiforme and Steven-Johnson syndrome and whether they are distinct entities or whether they represent a spectrum of one disease process. International collaborators have suggested that erythema multiforme and Steven-Johnson syndrome could be separated as 2 distinct clinical disorders with similar mucosal reactions but different patterns of cutaneous lesions.

The confusion between these 2 separate clinical entities began in 1950, when Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe conditions he encountered. Erythema multiforme minor was applied to patients with the illness originally described by Ferdinand von Hebra as erythema multiforme (acute, self-limited condition with characteristic red papular skin lesions) (1860). Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson (mucocutaneous disorder; febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption) (1922).
Up to 50% of patients with herpes simple virus (HSV)–associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than Steven-Johnson syndrome. Erythema multiforme and Steven-Johnson syndrome have different precipitating factors and different clinical patterns and are generally recognized to be separate clinical entities. Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme.
Consensus classification

According to a consensus definition, Steven-Johnson syndrome was separated from the erythema multiforme spectrum and added to toxic epidermal necrolysis. Essentially Steven-Johnson syndrome and toxic epidermal necrolysis (TEN) are considered severity variants of a single entity. The 2 spectra are now divided into the following: (1) erythema multiforme consisting of erythema minor and major and (2) Steven-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN).

The clinical descriptions are as follows:

    Erythema multiforme minor - Typical targets or raised, edematous papules distributed acrally
    Erythema multiforme major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).
    SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for Steven-Johnson syndrome / toxic epidermal necrolysis and 30% or more for toxic epidermal necrolysis.
Historical information

Stevens-Johnson syndrome was considered an extreme variant of erythema multiforme for many years, whereas toxic epidermal necrolysis (TEN) was considered a different entity. However, in 1993, a group of medical experts proposed a consensus definition and classification of erythema multiforme, Steven-Johnson syndrome, and toxic epidermal necrolysis based on a photographic atlas and extent of body surface area involvement.
See also Dermatologic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Oral Manifestations of Drug Reactions.
 Pathophysiology

The pathophysiology of erythema multiforme (EM) is still not completely understood, but it is probably immunologically mediated and appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.

Cell-mediated immunity appears to be responsible for the destruction of epithelial cells. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, whereas the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for < 30 d) a T-helper cell type 1 (TH1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF] alpha, interleukin [IL] 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

Other evidence supports the hypothesis that the disease is the result of cell-mediated immune reactions. Individuals possessing human leukocyte antigen (HLA)–B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response. 
Herpes simplex virus

A major cause of erythema multiforme is the herpes virus (HSV). In fact, recent or recurrent herpes has been reported as the principle risk factor for erythema multiforme.

Herpes-associated erythema multiforme (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen. The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8+ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are HLA-DR positive.

A relationship exists between HLA types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent erythema multiforme. In particular, HLA-DQ3 is especially related to recurrent erythema multiforme and may be a helpful marker for distinguishing HAEM from other cutaneous diseases.
Drug hypersensitivity

The disease process also often involves an abnormal metabolism of a responsible drug. As noted above, the keratinocyte is the ultimate target of this disease process, with keratinocyte necrosis being the earliest pathologic finding.

Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.
 Etiology

Many suspected etiologic factors have been reported to cause erythema multiforme (EM). Both erythema multiforme and Steven-Johnson syndrome may be induced by medications, but infectious agents are also considered to be a major cause of erythema multiforme. However, approximately 50% of cases are idiopathic, with no precipitating factor identified.

A previous history of erythema multiforme and male sex has also been reported as risk factors, but pregnancy may contribute to development of erythema multiforme as well.

Postvaccination causes include Bacille Calmette-Guérin (BCG) vaccination, oral polio vaccine, vaccinia, and tetanus/diphtheria. 
HSV and other infections

Infectious causes are more common in children and are implicated more commonly in erythema multiforme.

Erythema multiforme minor is regarded as being commonly triggered by herpes simplex virus (HSV) (types 1 and 2), and HSV is the most common cause in young adults; in fact, many instances of idiopathic erythema multiforme minor may be precipitated by subclinical HSV infection. Among other infections, Mycoplasma species appear to be a common cause.

Bacterial

Bacterial infections include borreliosis, catscratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, M pneumoniae, pneumococci, tuberculosis, Proteus/Pseudomonas/Salmonella/Staphylococcus/Yersinia species, Treponema pallidum, tularemia, Vibrio parahaemolyticus, Vincent disease, and rickettsial infections. Chlamydial infections include lymphogranuloma venereum and psittacosis.

Viral

Viral infections include Adenovirus, coxsackievirus B5, cytomegalovirus (CMV), echoviruses, enterovirus, Epstein-Barr virus (EBV), hepatitis A / B / C viruses (HAV / HBV / HCV), HSV, influenza, measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, varicella-zoster virus (VZV), and variola.

Virus-drug interactions include CMV infection–terbinafine and EBV infection–amoxicillin.
Other

Fungal infections include coccidioidomycosis, dermatophytosis, and histoplasmosis.

Parasitic infections include Trichomonas species and Toxoplasma gondii. 
Drugs

More than 50% of cases are related to medication use, but no test reliably proves the link between a single case and a specific drug.

Regarding medications, sulfa drugs are the most common triggers (30%). A slow acetylator genotype is a risk factor for sulfonamide-induced Steven-Johnson syndrome.
The second most commonly involved agents are the anticonvulsants, including barbiturates, carbamazepine, hydantoin, phenytoin, and valproic acid. Prophylactic anticonvulsants after surgery for a brain tumor combined with cranial irradiation may result in life-threatening Steven-Johnson syndrome.
Causative antibiotics include penicillin, ampicillin, tetracyclines, amoxicillin, cefotaxime, cefaclor, cephalexin, ciprofloxacin. erythromycin, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, and vancomycin.

Antituberculoid agents such as rifampicin, isoniazid, thiacetazone, and pyrazinamide are also known offenders. Antipyretic agents as triggers include analgesics, especially aspirin as well as phenylbutazone, oxyphenbutazone, and phenazone.

Others drugs that may cause erythema multiforme include acarbose, albendazole, allopurinol, arsenic, bromofluorene, quinine (Chinine), cimetidine, clofibrate, corticosteroids, diclofenac, didanosine, dideoxycytidine, diphosphonate, estrogen, etretinate, fluconazole, griseofulvin, gabapentin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hydralazine, indapamide, indinavir, lamotrigine, methazolamide, mefloquine, methotrexate, meprobamate, mercurials, minoxidil, nifedipine, nevirapine, nitrogen mustard, nystatin, nonsteroidal anti-inflammatory drugs (NSAIDs), phenolphthalein, piroxicam, pyritinol, progesterone, potassium iodide, sulindac, suramin, saquinavir, thiabendazole, thiouracil, terbinafine, theophylline, verapamil, and dihydrocodeine phosphate.
Contact exposure

Contactants include ammoniated mercury, budesonide, bufexamac, capsicum, chloromethylnaphthalene, desoximetasone, dinitrochlorobenzene (DNCB), disperse blue 124, diphenylcyclopropenone, fire sponge (Tedania ignis), herbal medicines (eg, Alpinia galanga), isopropyl-p -phenylenediamine of rubber, nickel, nitrogen mustard, oxybenzone, phenylbutazone, poison ivy, proflavin, resin, rosewood, and triamcinolone acetonide. 
Other etiologic factors

The following have also been reported as causes of erythema multiforme:

    Flavorings and preservatives, such as benzoic acid and cinnamon    Immunologic disorders, such as transient selective C4 deficiency of infancy, collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia
    Physical or mechanical factors, such as tattooing, radiotherapy, cold, and sunlight
    Foods, including salmon berries and margarine
    Malignancy
    Hormonal
Epidemiology

The exact incidence of erythema multiforme (EM) in the United States is unknown; however, as many as 1% of dermatologic outpatient visits are for erythema multiforme. Globally, the frequency of erythema multiforme is estimated at approximately 1.2-6 cases per million individuals per year.

Before the human immunodeficiency virus (HIV) epidemic among young males, there was a slight female predominance of this disease. However, erythema multiforme is currently more common in younger males (male-to-female ratio, range of 3:2 to 2:1) (mainly second to fourth decades, but can include children and adolescents [20%] ). The condition is rare in children younger than 3 years and in adults older than 50 years.

The following medical conditions seem to predispose individuals to a higher risk of developing the disorder: HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), and inflammatory bowel disease (IBD). Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk. 
Prognosis

Most cases of erythema multiforme (EM) are self-limited. In erythema multiforme minor, the lesions evolve over 1-2 weeks and ultimately subside within 2-3 weeks without scarring. However, the recurrence of erythema multiforme minor is common (up to one third of cases) and mostly preceded by apparent or subclinical herpes simplex virus (HSV) infection.

Erythema multiforme major has a mortality rate of less than 5% and is directly proportional to the total body surface area of sloughed epithelium. It usually has a more protracted course than erythema multiforme minor; clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after secondary infection. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.

Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors. Surprisingly, although the incidence of erythema multiforme is increased among individuals with human immunodeficiency virus (HIV) infection (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate. 
Continuous and persistent erythema multiforme

Two additional rare clinical forms of erythema multiforme have been reported. Continuous erythema multiforme manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids.

Persistent erythema multiforme has a protracted clinical course over months, is commonly associated with atypical skin lesions, and is commonly resistant to conventional treatment. It has been reported in association with inflammatory bowel disease (IBD), occult renal carcinoma, persistent or reactivated Epstein-Barr virus (EBV) infection, and HSV infection. 
Patient Education

Educate patients with erythema multiforme (EM) about appropriate symptomatic treatment, and provide reassurance that disease is usually self-limited. In addition, advise patients of the significant risk of recurrence and emphasize the avoidance of any identified etiologic agent. (See Monitoring and Prevention.)

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Urinary Continence in Children

Abstract and Introduction
Abstract

Achievement of urinary continence is an important developmental step that most children attain with the assistance of their parents and caregivers. Debate continues as to the best time to toilet train; in some Asian and African cultures children are trained as infants, while training at age 2-3 years is more typical in Western cultures. Infant voiding is not merely a spinal reflex, as the sensation of bladder filling is relayed to the brain. However, the ability of the brain to inhibit bladder contractions, and to achieve coordinated bladder contraction with sphincter relaxation, matures over time. While there is a concern that later toilet training may be responsible for an increase in urinary incontinence in children, no controlled studies on early versus late toilet training exist to evaluate this hypothesis. A number of medical conditions such as spina bifida, posterior urethral valves, cerebral palsy and autism can cause incontinence and difficulties in toilet training. The decision to start toilet training a child should take into account both the parents' expectation of how independent the child will be in terms of toileting, and the child's developmental readiness, so that a realistic time course for toilet training can be implemented.
Introduction


Toilet training is an important step for both children and parents, because it transitions the child to a more independent stage of life. The great majority of children and parents accomplish this without significant input from physicians, relying on practices that may be culturally determined, discussed in parenting magazines and books, or available on the Internet. Parents faced with a child that does not successfully toilet train often seek guidance from their pediatrician or primary care physician on the readiness of the child to begin toilet training, and how best to accomplish this successfully. Recommendations in western medical literature commonly rely on guidelines published by the American Academy of Pediatrics (AAP) in 1999, outlining the roles of parents, clinicians, and day-care providers in the process of toilet training. Studies performed in the 2000s indicate that the prevalence of urinary incontinence in children is approximately 6-9%. If the primary care physician is unable to determine a neurologic or metabolic cause for urinary incontinence (such as tethered spinal cord or diabetes insipidus), the child is usually referred to a pediatric urologist.

Parents seeking advice on toilet training their infant or toddler are faced with multiple options. Do they take the 'infant toilet training' approach, and pay close attention to their infant, positioning the child over the toilet or sink when he or she makes the tell-tale sign or noise that they need to urinate or defecate? Do they put the child on the toilet for a few minutes after each meal? Do they go along with standard medical recommendations, and wait until their child is 2 or 3 years old, leaving the child in diapers until then? Much of this information is dependent on cultural norms. Grandparents from non-Western cultures might remind parents that they were themselves toilet trained at a young age, using a variation of the first technique. While the 'infant toilet training' approach has received increased media attention in the past 5 years, it is still infrequently practiced in the US, and is not discussed in published guidelines from medical societies. Such anecdotes raise the question of whether the current recommendation to delay toilet training, based on the AAP guidelines, is a cultural practice, or if it is supported by scientific evidence. Changes in childcare over the past 50 years have complicated the process of toilet training, as it now involves both parents and childcare providers, who may use different approaches to toilet training. Some day-care providers require that a child be toilet trained before starting, reflecting the fact that the staffing ratio of care providers to children does not allow the same number of diaper changes that would be carried out at home. Therefore, the economics of childcare can also affect when parents start to toilet train their children.
This Review will focus on the achievement of urinary continence in children. The optimum age for toilet training will be discussed, using examples of variations in method between Western and non-Western cultures. This Review will also provide an overview of bladder function and voiding mechanisms in the infant and young child, will discuss factors in dysfunctional voiding, reviewing the hypothesis that delaying the age of toilet training may paradoxically cause urinary incontinence in children, and will overview medical disorders that may cause difficulty in achieving urinary continence
 Urinary Continence

The narrowest definition of urinary continence in a child would be merely the avoidance of unexpected voiding. From this viewpoint, an infant is capable of urinary continence if the caregiver is able to recognize when the infant needs to urinate. Some critics have called this "a reflex conditioning of the mother", a comment which reflects the reality that infant toilet training is time intensive and requires the continuous presence of a parent or caregiver. A broader definition, which is probably more in line with the expectations of parents and physicians, would include the ability of the child to sense when the bladder is full, inhibit the urge to urinate until a socially acceptable time and location, and independently use the toilet. This is the definition of urinary continence which will be used in this article. As this definition of continence requires that the child show significant communication, motor, and decision-making skills, toilet training to achieve these goals depends not only on the maturity of the central nervous system and bladder to store, detect and empty urine, but also on the child's overall development.
 Toilet Training

Toilet training is the process of achieving both urinary and stool continence. Infant (less than 1 year old) or early toilet training is not directly comparable with late toilet training (children aged 18 months or over), since both the timing and expected outcome are different. In early toilet training, the goal is to learn when the child needs to void, so that he or she can be brought to the toilet, while the goal of late toilet training is for the child to be completely independent in the entire process of toileting. In the late 19th century, infant toilet training using mechanical stimulants such as soap or laxatives, or rectal stimulation, was popular in the US. The preference for late toilet training returned in the 1930s when concerns were raised about relapses back to incontinence following early toilet training. A 1962 paper by Brazleton and a 1974 book by Foxx and Azrin both emphasized the value of starting toilet training when the child was developmentally ready (known as the 'child-centered approach'), which laid the foundations for the current recommendation to wait until the child is at least 18 months old before starting toilet training, as by this age the child is able to relay the sensation of bladder fullness to their parent. The Foxx-Azrin approach is more intensive and structured than that of Brazleton, and begins with demonstration of toileting to the child using a doll, followed by increased fluid intake and scheduled toilet times. Correct behavior is reinforced with rewards such as food, hugs and toys, while accidents are over-corrected by verbal reprimand, loss of reinforcements, and additional practice sessions. The Brazleton approach begins by sitting the child on the potty clothed, followed by sitting without a diaper. Stool and urine are emptied into the potty, explaining to the child that this is where they go; the final stage is independent use of the potty by the child. Foxx and Azrin reported that continence can be achieved in 4 h in appropriately selected children, while children who are toilet trained using the Brazleton approach appear to take between 6 and 18 months to achieve urinary continence.
Retrospective questionnaires investigating age at toilet training are subject to significant recall bias; the best data from Western countries come from two longitudinal cohort studies performed in Switzerland in the late 1950s and the 1970s. In these studies, stool continence was achieved first at the age of 3 years in 97% of the group, followed by daytime urinary continence in 97% of the group by the age of 6 years, and finally night-time urinary continence. In total, 90% of boys and 94% of girls had achieved complete night-time urinary continence by the age of 6 years. Although toilet training was started at 6-12 months of age in the 1950s cohort, and 12-18 months of age in the 1970s cohort, daytime urinary continence was achieved in 90% of both groups by 4 years of age, and 97% of both groups by 6 years of age. These results were replicated in another longitudinal cohort of children born in 1952, from Baltimore in the USA, with exactly the same percentages seen at the same ages. Nowadays, completion of toilet training before starting kindergarten at approximately 5 years of age would be considered a normal age in children. A more recent prospective study using the child-centered approach in middle class families was conducted in 2003. Children were recruited between 17 and 19 months of age, and parents began toilet training them at a mean age of 29 months. Children who started toilet training before 27 months of age achieved urinary continence at the same time as those who started after 27 months; an average of 37 months.
Many Asian, African, and South American countries show a cultural preference for early toilet training of infants, but other than case reports, no data on age of completion of toilet training and urinary incontinence are available. The most quoted paper in this context describes the toilet training practices of the Digo people of Kenya. These practices are similar to infant toilet training, with the expectation of daytime and nighttime urinary continence by 6 months of age. The mother positions the child between her legs and makes a "shuus" sound that the child learns to link with urinating. Mothers are able to tell that their child is ready to urinate based on the sounds and movements made by the child. This approach combines a stimulus (sound) with the conditioned response (urination), assisted by the mother's perception of when the child needs to void. The authors note that cultural acceptance of public urination, uncumbersome clothes, and the ability of the mother to spend the entirety of the first 2 months of the child's life with her infant contribute to the success of this approach. A study from Vietnam suggests that infant toilet training results in a decreased postvoid residual volume by 9 months, which may indicate that infants can empty their bladders more efficiently if toilet training is undertaken. If this initial finding can be confirmed in other populations, it could indicate that early toilet training might be an important tool for children with anatomical abnormalities such as vesicoureteral reflux, which put them at higher risk for urinary tract infection. Longer-term follow-up on participants who undergo infant toilet training is not currently available.
 
If one considers the three-part definition of continence outlined earlier (sensing a full bladder; inhibiting the urge to urinate until socially acceptable; and independent use of the toilet or potty), a combination of developmental skills indicate when a child is ready to be toilet trained. Generally, not having bowel movements at night, noticing the urge to void or to pass stool, communicating the need to go to the toilet, being dry for periods of at least 2 h, and waking up dry from a nap, are prerequisites in a child-centered approach to toilet training. These skills are achieved at a median of 22 months in girls, and at 25 months in boys, when they become continent of stool at night. The AAP recommends that toilet training can be started when the child is aged 18 months, but children will reach these developmental milestones at different times; girls acquire almost all the developmental skills related to toilet training at an earlier age than boys.

The role of stress and behavior in toilet training was studied in a group of children aged 4 years or older, who were unsuccessful at toilet training for more than 6 months, or who refused to use the toilet. Although parenting styles (laxness, verbosity, over-reactivity) were not different between the difficult to train and control groups, children who were characterized as difficult personalities by behavioral questionnaire (less adaptable, negative mood, less persistent) were more likely to be difficult to toilet train. Parental stress (isolation, depression, spousal relationship issues) does not seem to influence the age of the child on toilet training, but refusal to stool in a toilet, constipation, and hiding when defecating are more frequent in children who toilet trained after 42 months of age 
Bladder Function and Voiding Mechanisms

The natural history of infant bladder function was first systematically studied in the 1990s using free voiding studies and urodynamics. The human neonate initially voids small amounts, about once an hour. Bladder capacity increases in two growth spurts: the first at birth, the second at 3 years of age. Neonates were previously believed to urinate while sleeping as well as when awake, suggesting that a local sacral reflex was responsible for emptying the bladder. However, analysis of neonatal electroencephalography tracings suggests that most neonates experience some arousal before voiding, indicating that the brain is always involved when the bladder empties. Infants experience interrupted (or incomplete) voiding as a result of lack of coordination between the bladder and the external sphincter, which causes elevated voiding pressures until the child reaches the age of 18 months. At 1 week of age, boys void with mean detrusor pressures of 117 cm H2O, and girls with pressures of 75 cm H2O.The traditional belief that the urinary frequency seen in the infant bladder was due to overactivity was disproved by the rarity of overactive contractions observed during studies of infant urodynamics carried out in asymptomatic children.

The high bladder pressures and progressive control of the bladder by the brain in the human infant matches that of the neonatal rat, allowing a great degree of translation from experimental animal findings to humans. It is not ethically possible to obtain bladder tissue from healthy human infants or interfere with their neural maturation, therefore much of what we understand about the neonatal bladder is derived from experimental models. Neonatal cats, rats, and mice are unable to void spontaneously, and are dependent on their mother to lick the perigenital area to cause the bladder to empty. By 3 weeks of age, when they are weaned, neonatal rats are able to void spontaneously in response to bladder filling. At first glance, these findings suggest that the neonatal nervous system is not mature enough for animals to void spontaneously. As the perigenital-bladder reflex reemerges after spinal cord injury, however, and bladder emptying in response to filling can occur in neonatal rats if the forebrain is disconnected from the brainstem, the perigenital reflex actually inhibits the mature bladder emptying reflex. This inhibition is removed at the time of weaning, allowing the rat to void spontaneously. Experimental bladder distension similarly results in the onset of spontaneous voiding at 3 weeks, but prolongs the perigenital reflex for another 2 weeks. Surgical reduction of bladder volume causes the immediate onset of spontaneous voiding in neonatal rats, and results in a long-term increase in bladder capacity and lower voiding pressures. These findings suggest that coordination between the bladder and sphincter requires maturation of central neural control, and that peripheral nervous system connections are ready for use at birth.

While human infants do not exhibit the perigenital reflex, they will void in response to stroking of the paravertebral muscles until 2 months of age.Perhaps infant toilet training activates a primitive bladder emptying reflex via stimuli provided by the mother, while the mature bladder emptying reflex in response to filling requires control exerted by the child's forebrain. Previously, neonatal bladder emptying was thought to only involve an isolated sacral spinal cord reflex, but animal data suggest that bladder emptying in neonates involves descending control from the forebrain to the brainstem, all the way down to the bladder.
The other key finding from animal studies is that neonatal bladder smooth muscle functions differently to that in older juvenile animals and children. Animal study findings indicate that the neonatal bladder produces more pressure per gram of tissue, is more dependent on local calcium levels, and has large-amplitude spontaneous contractions, which become downregulated with maturation.The elevated voiding pressures seen in infants may therefore also represent immature smooth muscle function. The neonatal bladder empties well, but does not store well in both rats and humans. The spontaneous contractions observed in the neonatal rat bladder occur only when central regulation of the bladder is removed, suggesting that the brain exerts a tonic inhibition on the bladder. In children, a high-capacity bladder and small postvoid residual volume seem to predict earlier completion of toilet training, which likely means that central control of the bladder is more effective when the bladder demonstrates mature smooth muscle function 
Urinary Incontinence

A comparison of different toilet training methods and timings has suggested that the modern trend for late toilet training may have caused an increase in the diagnosis of urinary incontinence. It is unclear whether we are diagnosing urinary incontinence more commonly because we are more aware of it, if urinary incontinence and late toilet training are both increasing but unrelated, or if late toilet training is a cause of urinary incontinence. In these studies, children with persistent daytime and night-time incontinence had begun toilet training at an older age (greater than 18-24 months) than the children who were dry. Limitations of these studies included retrospective design,and a varying definition of late toilet training (age greater than 18 months, or age greater than 24 months) between studies. A retrospective survey of schoolchildren at a mean age of 11.5 years found that children with daytime urinary incontinence tended to start toilet training 6 months later than those without, although the median age for starting toilet training in both groups was 18-24 months. A prospective study designed to investigate environmental effects on children's health was reanalyzed to evaluate the age that toilet training was initiated, which was then compared with the child's daytime continence at 9 years of age. 50% of parents in the study reported starting toilet training when their child was between 15 and 24 months of age. Only 2% had started by the time their child had reached the age of 6 months, and 14% started when their child was aged between 6 and 15 months; the outcomes in this group were no different to those in the 15-24 month group. Children who started toilet training after 24 months of age were more likely to have persistent daytime incontinence than those in the 15-24 month group. Since the study was not initially designed to evaluate this question, no data about toilet training at 18 months was available.An alternative conclusion from the last 2 studies might be that the parents of children with persistent incontinence had delayed toilet training because the children had not reached the appropriate developmental milestones.

Current understanding of dysfunctional voiding based on physiological principles proposes that the root cause is failure to relax the external urethral sphincter.Patients with dysfunctional voiding exhibit excessive urethral sphincter and pelvic floor activity, and it has been hypothesized that persistence of an immature stage of bladder and sphincter control is responsible.As lack of coordination between the bladder and sphincter is a normal developmental phase, the failure of a child to achieve normal coordination at 18 months of age has been proposed as a key point at which dysfunctional voiding (or non-neurogenic bladder dysfunction) could develop. A key factor in the acquisition of urinary continence that has not been studied is the age at which children gain the ability to voluntarily suppress the urge to void (the guarding reflex). This information will probably never be obtained, as children are gaining language skills at the same time that they are achieving this process so are unable to accurately communicate this. As the guarding reflex is capable of shutting off bladder contractions, dysfunctional voiding might arise because children over-learn the ability to contract the external urethral sphincter during toilet training, and never learn to relax their sphincter correctly, allowing the neonatal lack of coordination between bladder and sphincter to persist. A larger than normal bladder capacity could lead either to a high-capacity, compliant bladder with poor emptying, or a hypertrophied bladder with overactive contractions. Progressive loss of bladder sensation can occur with either of these disorders, making the child less likely to void at the proper time. No clinical studies have proved that early or late toilet training is more likely to cause urinary incontinence or dysfunctional voiding. While it is reasonable to assume that a sphincter which cannot completely relax, or a bladder that empties inefficiently are due to persistently immature sphincter and bladder function, the role that toilet training plays in this persistence remains unclear.

The persistence of childhood urinary incontinence as a cause of adult urinary incontinence has been suggested, based on retrospective surveys. As asking women with urinary incontinence to remember the severity of their childhood incontinence is subject to recall bias, prospective follow-up studies on children diagnosed with urinary incontinence into adult life would confirm this hypothesis and show if any spontaneous resolution of urinary incontinence occurs. If childhood treatment for urinary incontinence was found to prevent this morbidity in adults, it would provide additional incentive to treat during childhood. 
Incontinence in Medical Disorders

A number of patient populations have difficulty achieving urinary continence as a consequence of a medical disorder or surgery. Treatment for these patients does not follow a one-size-fits-all approach, but should be specifically tailored to the individual.

Anticholinergic medications, such as oxybutynin, are commonly used to treat urinary incontinence due to bladder overactivity (cerebral palsy, posterior urethral valves) or hyperactivity (spina bifida). They act by relaxing the smooth muscle of the bladder, enabling it to store more urine at low pressures. Anticholinergic medications do not affect bladder sphincter coordination, nor do they relax the urethral sphincter. Spina Bifida

Patients with spina bifida have difficulty with bladder storage, bladder sensation, and toileting. Abnormal efferent innervation of the bladder leads to inadequate storage capacity or to high-pressure storage and emptying, which may lead to renal insufficiency and hypertension, and the abnormal afferent nerves have reduced ability to sense bladder fullness. Patients with spina bifida may also have difficulty with multistep tasks, such as intermittent catheterization for bladder emptying, or administration of an antegrade continence enema. Management of urinary continence in these patients focuses on turning the bladder into an appropriate storage organ by using anticholinergic medications, bypassing the sphincter with intermittent catheterization at safe volumes (pressures below 20 cm H2O), patient education, and continued monitoring of bowel and bladder management throughout adulthood. While there are varying degrees of urinary continence in patients with spina bifida, management of urinary incontinence is secondary to maintenance of normal renal function, and is dependent on the patient's level of function. High-functioning patients with spina bifida will likely choose surgical procedures to gain social urinary continence during adolescence so that they may achieve greater independence as adults Patients who are not able to reliably perform catheterization may remain incontinent so that their renal function is not threatened.
Posterior Urethral Valves

Posterior urethral valves (PUVs) affect boys, and are caused by an obstructing membrane in the prostatic urethra. They are often detected prenatally, but can also present as failure to toilet train in the older boy, as they prevent normal bladder emptying. Surgical management involves endoscopic ablation of the valves postnatally, and occasionally supravesical diversion. Patients with PUVs have variable bladder function after initial valve ablation, which might account for the universal delay in toilet training in these individuals. The obligate diuresis caused by poor renal concentrating ability and polyuria in patients with PUVs results in a bladder that does not appropriately signal fullness. Only 50% of patients with PUVs achieve urinary continence by 10 years of age, although there is a progressive improvement in continence as the patient reaches adulthood. Patients with an overactive bladder will require anticholinergic medication to reduce bladder pressures while maintaining adequate emptying, while patients with incomplete emptying initially use behavioral therapies such as timed voiding and double voiding to empty the bladder before additional stretch injury can occur. Patients with a flaccid bladder might need α-blockers or intermittent catheterization to overcome their inability to empty. The aim of these maneuvers is to improve the efficiency of bladder emptying, but if there is worsening hydronephrosis or an increase in serum creatinine, clean intermittent catheterization is usually started. Overnight catheter drainage is effective in improving hydronephrosis and renal function, if patient bladder control does not improve with initial behavioral therapy.
Cerebral Palsy

The main cause of urinary incontinence in children with cerebral palsy is lack of executive function, and inability to suppress the urge to void. The degree of urinary incontinence varies with cerebral palsy severity, partly due to the communication problems that exist for more severely affected patients. Approximately one-third of patients with cerebral palsy will require urologic evaluation. Medical treatment with anticholinergic medications can be successful in creating a larger functional bladder capacity. While patients with cerebral palsy can sense a full bladder, they might have difficulty expressing the sensation clearly to their caregivers. In an approach similar to that taken with infant toilet training, understanding how the child expresses his or her sensation of bladder fullness is important, so that they can get to a toilet in time. Limb weakness, spasticity, and tendon contractures can make it difficult for patients with cerebral palsy to toilet independently, and family members and caregivers should be given a realistic idea of what level of urinary continence the patient is capable of achieving. A child can sometimes be dry at home when the parents are able to rapidly get them to a toilet, but be wet at school because the number of children per caregiver is higher. Urinary incontinence may persist into adult life in some patients.
Autism

Children with autism are extremely challenging to toilet train. While their bladder storage and emptying function should be normal, their individual response to bladder filling is unpredictable. Some children have sensory issues, and find the sensation of bladder contraction unbearable; these patients might require anticholinergic medications to increase the interval between voiding. Others might completely ignore the signals from their bladder and wet themselves because their attention is focused elsewhere. The system of timed and double voiding that works well in patients with PUVs can be difficult to implement in a child with autism, if he or she finds the sounds and smells of the bathroom disturbing. Although the literature in this area is scant, the structured Foxx-Azrin child-centered approach to toilet training seems to be most successful in achieving urinary continence in children with autism. Success in achieving toilet training is variable in children with autism, and is dependent on both the severity and type. 
Conclusions

The age at which children successfully achieve urinary continence can be affected by many factors, including parental expectations, developmental stage of the child, and medical disorders. The optimum age for toilet training is still uncertain. No trial has compared different methods of toilet training, nor have studies told us when the optimum time for toilet training should be. Longitudinal studies reflect the current practices of toilet training, rather than comparing different methods or timings. Early toilet training has obvious benefits, but requires an investment of time, along with cultural norms that do not require children to void in a toilet. The experience of early toilet training in non-Western cultures suggests that it can be done successfully, although long-term outcomes of urinary continence are not reported. Toilet training after 18 months of age in Western cultures minimizes the length of training by starting when a child has met certain developmental milestones, but is dependent on convenience factors, such as the availability of cheap, disposable diapers, or suitable washing facilities for soiled clothing and diapers.

A child's bladder and sphincter function show increased maturity at approximately 18 months of age, but whether toilet training should occur before or after this milestone remains unclear. Available data suggest that toilet training is easier to achieve when the bladder is more stable and the brain is capable of making the bladder and sphincter work in concert; the timing of voluntary control over voiding is also difficult to change.

As parents from all cultures find toilet training a challenge, our most appropriate approach as physicians might be to first identify the parents' expectations of toilet training and then discuss a toilet training regimen based on the available knowledge and methods that best fit the parents and child. Information on various toilet training methods can be provided to enable the parents to estimate how long the process will take, and what obstacles will be encountered. There is not enough available information to determine how long infant toilet training should take, aside from the expectation that it should be accomplished by the age of 6-12 months. No evidence exists that it is harmful to begin toilet training early, as long as the parents are willing to invest the time in doing so. If early toilet training is undertaken, the child will still need to learn the skills associated with independent toileting at the age of 2-3 years. If the parents prefer to wait until the child is older, and implement a method that allows the child to be completely independent in terms of toileting, then assessment of the child's developmental milestones and interest in toilet training is a good place to start. If the parents discover that their child is having significant difficulty with toilet training, then the ability of the parents to understand and implement their chosen method of toilet training should be evaluated, and the child should be examined to rule out the presence of any medical conditions that may delay toilet training.

Further investigation into the transition from immature to mature bladder function in neonatal animals may determine the mechanisms which delay the acquisition of urinary continence in children with medical disorders. Long-term evaluation of bladder function in children trained as infants, at 18 months, or later, will eventually prove or disprove the hypothesis that late toilet training is creating a generation of children with urinary incontinence. While it is tempting to attribute success in toilet training purely to the time and method chosen, the child's personality and physiological readiness to toilet train will also clearly affect how long the process will take.

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Measles Clinical Presentation

History

The patient history is notable for exposure to the virus. The incubation period from exposure to onset of measles symptoms ranges from 7 to 14 days (average, 10-12 days). Patients are contagious from 1-2 days before the onset of symptoms. Healthy children are also contagious during the period from 3-5 days before the appearance of the rash to 4 days after the onset of rash. On the other hand, immunocompromised individuals can be contagious during the duration of the illness. 

The first sign of measles is usually a high fever (often >104^o F [40^o C]) that typically lasts 4-7 days. This prodromal phase is marked by malaise, fever, anorexia, and the classic triad of conjunctivitis (see the image below), cough, and coryza (the “3 Cs”). Other possible associated symptoms include photophobia, periorbital edema, and myalgias.

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Measles conjunctivitis The characteristic enanthem generally appears 2-4 days after the onset of the prodrome and lasts 3-5 days. Small spots (Koplik spots) can be seen inside the cheeks during this early stage (see the image below).

Koplik spots in measles. Photograph courtesy of World Health Organization. The exanthem usually appears 1-2 days after the appearance of Koplik spots; mild pruritus may be associated. On average, the rash develops about 14 days after exposure, starting on the face and upper neck (see the image below) and spreading to the extremities. Immunocompromised patients may not develop a rash.
Child with measles. Photograph courtesy of Centers for Disease Control and Prevention. The entire course of uncomplicated measles, from late prodrome to resolution of fever and rash, is 7-10 days. Cough may be the final symptom to appear.

Modified and atypical measles

Modified measles is a milder form of measles that occurs in individuals who have received serum immunoglobulin after their exposure to the measles virus. Similar but milder symptoms and signs may still occur, but the incubation period may be as long as 21 days.
Atypical measles occurs in individuals who were vaccinated with the original killed-virus measles vaccine between 1963 and 1967 and who have incomplete immunity. After exposure to the measles virus, a mild or subclinical prodrome of fever, headache, abdominal pain, and myalgias precedes a rash that begins on the hands and feet and spreads centripetally. The eruption is accentuated in the skin folds and may be macular, vesicular, petechial, or urticarial. The live-attenuated vaccine replaced the killed vaccine in 1967 and is not associated with atypical measles.

Physical Examination

Enanthem

 

Near the end of the prodrome, Koplik spots (ie, bluish-gray specks or “grains of sand” on a red base) appear on the buccal mucosa opposite the second molars (see the image below).

 

Enanthem of measles (Koplik spots) The Koplik spots generally are first seen 1-2 days before the appearance of the rash and last until 2 days after the rash appears. This enanthem begins to slough as the rash appears. Although this is the pathognomonic enanthem of measles, its absence does not exclude the diagnosis.

Exanthem

Blanching, erythematous macules and papules begin on the face at the hairline, on the sides of the neck, and behind the ears (see the images below). Within 48 hours, they coalesce into patches and plaques that spread cephalocaudally to the trunk and extremities, including the palms and soles, while beginning to regress cephalocaudally, starting from the head and neck. Lesion density is greatest above the shoulders, where macular lesions may coalesce. The eruption may also be petechial or ecchymotic in nature.
Face of boy with measles Morbilliform rash Patients appear most ill during the first or second day of the rash. The exanthem lasts for 5-7 days before fading into coppery brown hyperpigmented patches, which then desquamate. The rash may be absent in patients with underlying deficiencies in cellular immunity.

Complications

Most complications of measles occur because the measles virus suppresses the host’s immune responses, resulting in a reactivation of latent infections or superinfection by a bacterial pathogen. Consequently, pneumonia, whether due to the measles virus itself, to tuberculosis, to or another bacterial etiology, is the most frequent complication. Pleural effusion, hilar lymphadenopathy, hepatosplenomegaly, hyperesthesia, and paresthesia may also be noted. 

 

Complications of measles are more likely to occur in persons younger than 5 years or older than 20 years, and complication rates are increased in persons with immune deficiency disorders, malnutrition, vitamin A deficiency, and inadequate vaccination. Immunocompromised children and adults are at increased risk for severe infections and superinfections.
Common infectious complications include otitis media, interstitial pneumonitis,^[19] bronchopneumonia, laryngotracheobronchitis (ie, croup), exacerbation of tuberculosis, transient loss of hypersensitivity reaction to tuberculin skin test, encephalomyelitis, diarrhea, sinusitis, stomatitis, subclinical hepatitis, lymphadenitis, and keratitis, which can lead to blindness. In fact, measles remains a common cause of blindness in many developing countries.
Rare complications include hemorrhagic measles, purpura fulminans, hepatitis, disseminated intravascular coagulation (DIC), subacute sclerosing panencephalitis (SSPE), thrombocytopenia, appendicitis, ileocolitis, pericarditis, myocarditis, acute pancreatitis,^[20] and hypocalcemia.^[21] Transient hepatitis may occur during an acute infection.
Approximately 1 of every 1,000 patients develops acute encephalitis, which often results in permanent brain damage and is fatal in about 10% of patients. In children with lymphoid malignant diseases, delayed-acute measles encephalitis may develop 1-6 months after the acute infection and is generally fatal.
An even rarer complication is SSPE, a degenerative CNS disease that can result from a persistent measles infection. SSPE is characterized by the onset of behavioral and intellectual deterioration and seizures years after an acute infection (the mean incubation period for SSPE is approximately 10.8 years).
The complications of measles in the pregnant mother include pneumonitis, hepatitis, subacute sclerosing panencephalitis, premature labor, spontaneous abortion, and preterm birth of the fetus. Perinatal transmission rates are low

References

1. Sabella C. Measles: not just a childhood rash. Cleve Clin J Med. Mar 2010;77(3):207-13. [Medline].
2. [Guideline] Centers for Disease Control and Prevention. Recommended immunization schedules for persons aged 0 through 18 years---United States, 2009. CDC Recommended Vaccine Schedule. Dec 2008;57(51;52):[Full Text].
3. Meissner HC, Strebel PM, Orenstein WA. Measles vaccines and the potential for worldwide eradication of measles. Pediatrics. 2004;114(4):1065-9. [Medline]. [Full Text].
4. Smeeth L, Cook C, Fombonne E, et al. MMR vaccination and pervasive developmental disorders: a case-control study. Lancet. 2004;11-17;364(9438):963-9. [Medline].
5. Schneider-Schaulies S, Schneider-Schaulies J. Measles virus-induced immunosuppression. Curr Top Microbiol Immunol. 2009;330:243-69. [Medline].
6. Markowitz LE, Preblud SR, Fine PE, Orenstein WA. Duration of live measles vaccine-induced immunity. Pediatr Infect Dis J. Feb 1990;9(2):101-10. [Medline].
7. Reported vaccine-preventable diseases--United States, 1993, and the childhood immunization initiative. MMWR Morb Mortal Wkly Rep. Feb 4 1994;43(4):57-60. [Medline].
8. Orenstein WA, Papania MJ, Wharton ME. Measles elimination in the United States. J Infect Dis. May 1 2004;189 Suppl 1:S1-3. [Medline].
9. Coleman KP, Markey PG. Measles transmission in immunized and partially immunized air travellers. Epidemiol Infect. Jul 2010;138(7):1012-5. [Medline].

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Measles

Measles, also known as rubeola, is one of the most contagious infectious diseases, with at least a 90% secondary infection rate in susceptible domestic contacts. It can affect people of all ages, despite being considered primarily a childhood illness. Measles is marked by prodromal fever, cough, coryza, conjunctivitis, and pathognomonic enanthem (ie, Koplik spots), followed by an erythematous maculopapular rash on the third to seventh day. Infection confers life-long immunity.


A generalized immunosuppression that follows acute measles frequently predisposes patients to bacterial otitis media and bronchopneumonia. In approximately 0.1% of cases, measles causes acute encephalitis. Subacute sclerosing panencephalitis (SSPE) is a rare chronic degenerative disease that occurs several years after measles infection.

After an effective measles vaccine was introduced in 1963, the incidence of measles decreased significantly. Nevertheless, measles remains a common disease in certain regions and continues to account for nearly 50% of the 1.6 million deaths caused each year by vaccine-preventable childhood diseases. The incidence of measles in the United States and worldwide is increasing, with outbreaks being reported particularly in populations with low vaccination rates.
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Maternal antibodies play a significant role in protection against infection in infants younger than 1 year and may interfere with live-attenuated measles vaccination. A single dose of measles vaccine administered to a child older than 12 months induces protective immunity in 95% of recipients. Because measles virus is highly contagious, a 5% susceptible population is sufficient to sustain periodic outbreaks in otherwise highly vaccinated populations.


A second dose of vaccine, now recommended for all school-aged children in the United States,[2] induces immunity in about 95% of the 5% who do not respond to the first dose. Slight genotypic variation in recently circulating strains has not affected the protective efficacy of live-attenuated measles vaccines.

Unsubstantiated claims that suggest an association between the measles vaccine and autism have resulted in reduced vaccine use and contributed to a recent resurgence of measles in countries where immunization rates have fallen to below the level needed to maintain herd immunity.


Considering that for industrialized countries such as the United States, endemic transmission of measles may be reestablished if measles immunity falls to less than 93-95%, efforts to ensure high immunization rates among people in both developed and developing countries must be sustained.


Supportive care is normally all that is required for patients with measles. Vitamin A supplementation during acute measles significantly reduces risks of morbidity and mortality.


For patient education resources, see Bacterial and Viral Infections, as well as Measles and Skin Rashes in Children
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Etiology

The cause of measles is the measles virus, a single-stranded, negative-sense enveloped RNA virus of the genus Morbillivirus within the family Paramyxoviridae. Humans are the natural hosts of the virus; no animal reservoirs are known to exist. This highly contagious virus is spread by coughing and sneezing via close personal contact or direct contact with secretions.

Risk factors for measles virus infection include the following:

Children with immunodeficiency due to HIV or AIDS, leukemia, alkylating agents, or corticosteroid therapy, regardless of immunization status
Travel to areas where measles is endemic or contact with travelers to endemic areas
Infants who lose passive antibody before the age of routine immunization

Risk factors for severe measles and its complications include the following:

Malnutrition
Underlying immunodeficiency
Pregnancy
Vitamin A deficiency
Epidemiology
United States statistics


The practice of administering 2 doses of live-attenuated measles vaccine to children to prevent school outbreaks of measles was implemented when the vaccine was first licensed in 1963. The immunization program resulted in a decrease of more than 99% in reported incidence.


From 1989 to 1991, a major resurgence occurred, affecting primarily unvaccinated preschoolers. This measles resurgence resulted in 55,000 cases and 130 deaths[7] and prompted the recommendation that a second dose of measles vaccine be given to preschoolers in a mass vaccination campaign that led to the effective elimination in the United States of endemic transmission of the measles virus.[8]


By 1993, vaccination programs had interrupted the transmission of indigenous measles virus in the United States; since then, most reported cases of measles in the United States have been linked to international travel.[9] By 1997-1999, the incidence of measles had been reduced to a historic low (< 0.5 cases per million persons). From 1997 to 2004, the reported incidence was as low as 37-116 cases per year. From November 2002 on, measles was not considered an endemic disease in the United States.


From 2000 through 2007, an average of 63 cases were reported annually to the US Centers for Disease Control and Prevention (CDC). In 2004, 34 cases were reported; after that all-time low, however, the annual incidence began to increase, with most cases linked either directly or indirectly to international travel. Incomplete vaccination rates facilitate the spread once the virus is imported to the United States.


In 2005, 66 cases of measles were reported to the CDC.[10] Of these, 34 were linked with a single outbreak in Indiana associated with the return of an unvaccinated 17-year-old American traveling in Romania. In 2006, a total of 49 confirmed cases were reported in the United States.


From January to June 2008, 131 cases of measles were reported to the CDC.[11] Although 90% of those 131 cases were associated with importation of the virus to the United States from overseas, 91% of those affected were unvaccinated or had unknown or undocumented vaccination status. At least 47% of the 131 measles infections were in school-aged children whose parents chose not to have them vaccinated.[11]


In the period from January 1 to May 20, 2011, a total of 118 cases were reported to the CDC; this represents the highest reported number of measles cases for the same period since 1996.[12] Of the 118 cases, 105 (89%) were associated with importation; the source of the remaining 13 cases could not be ascertained. In all, 105 (89%) of the 118 patients were unvaccinated; 24 (20%) were persons 12 months to 19 years of age whose parents claimed a religious or personal exemption.


Approximately half of the 118 cases—58, or 49%—were accounted for by 9 outbreaks. The largest of these outbreaks involved 21 persons in Minnesota, in a setting where parental concerns about the safety of measles, mumps, and rubella (MMR) vaccine caused many children to go unvaccinated.[13] As a result of this outbreak, many persons were exposed, and at least 7 infants too young to receive MMR vaccine were infected.


Despite the highest recorded immunization rates in history, young children who are not appropriately vaccinated may experience more than a 60-fold increase in risk of disease due to exposure to imported measles cases from countries that have not yet eliminated the disease.
International statistics


In developing countries, measles affects 30 million children a year and causes 1 million deaths. Measles causes 15,000-60,000 cases of blindness per year.


In 1998, the cases of measles per 100,000 total population reported to the World Health Organization (WHO) was 1.6 in the Americas, 8.2 in Europe, 11.1 in the Eastern Mediterranean region, 4.2 in South East Asia, 5.0 in the Western Pacific region, and 61.7 in Africa. In 2006, only 187 confirmed cases were reported in the Western Hemisphere (mainly in Venezuela, Mexico, and the United States).[14]


Between 2000 and 2008, the number of worldwide measles cases reported to the WHO and the United Nations Children’s Fund (UNICEF) declined by 67% (from 852,937 to 278,358). During the same 8-year period, global measles mortality dropped by 78%. However, it is believed that global measles incidence and mortality remain underreported, with many countries, particularly those with the highest disease burden, lacking complete, reliable surveillance data.[15]


Since 2008, France has been experiencing an outbreak of measles, which has not yet begun to slacken.[16] Over the same period, outbreaks have also been occurring in the 46 countries of the WHO African Region.[17] Worldwide, most reported cases of measles continue to be from Africa.
Age-related demographics


Although measles is historically a disease of childhood, infection can occur in unvaccinated or partially vaccinated individuals of any age or in those with compromised immunity.


Unvaccinated young children are at the highest risk. Age-specific attack rates may be highest in susceptible infants younger than 12 months, school-aged children, or young adults, depending on local immunization practices and incidence of the disease. Complications such as otitis media, bronchopneumonia, laryngotracheobronchitis (ie, croup), and diarrhea are more common in young children.


Of the 66 cases of measles reported in the United States in 2005, 7 (10.6%) involved infants, 4 (6.1%) involved children aged 1-4 years, 33 (50%) involved persons aged 5-19 years, 7 (10.6%) involved adults aged 20-34 years, and 15 (22.7%) involved adults older than 35 years.[10]


Among the 118 US patients reported to have measles between January 1 and May 20, 2011, age ranged from 3 months to 68 years.[12] More than half were younger than 20 years: 18 (15%) were younger than 12 months, 24 (20%) were 1-4 years old, 23 (19%) were 5-19 years old, and 53 (45%) were 20 years of age or older.


In heavily populated, underdeveloped countries, measles is most common in children younger than 2 years.

Sex- and race-related demographics

Unvaccinated males and females are equally susceptible to infection by the measles virus. Excess mortality following acute measles has been observed among females at all ages, but it is most marked in adolescents and young adults. Excessive non–measles-related mortality has also been observed among female recipients of high-titer measles vaccines in Senegal, Guinea Bissau, and Haiti.[18]


Measles affects people of all races.

Prognosis

The prognosis for measles is generally good, with infection only occasionally being fatal. The CDC reports the childhood mortality rate from measles infection in the United States to be 0.1-0.2%. However, many complications and sequelae may develop (see Complications), and measles is a major cause of childhood blindness in developing countries.


Globally, measles remains one of the leading causes of death in young children. According to the CDC, measles caused an estimated 197,000 deaths worldwide in 2007.[14] An estimated 85% of these deaths occurred in Africa and Southeast Asia. From 2000-2007, deaths worldwide fell by 74% (to 197,000 from an estimated 750,000), thanks to the partnership of several global organizations.


Case-fatality rates are higher among children younger than 5 years. The highest fatality rates are among infants aged 4-12 months and in children who are immunocompromised because of human immunodeficiency virus (HIV) infection or other causes.


Complications of measles are more likely to occur in persons younger than 5 years or older than 20 years, and morbidity and mortality are increased in persons with immune deficiency disorders, malnutrition, vitamin A deficiency, and inadequate vaccination.


Croup, encephalitis, and pneumonia are the most common causes of death associated with measles. Measles encephalitis, a rare but serious complication, has a 10% mortality.

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Scarlet Fever

Scarlet Fever
Scarlet fever is an upper respiratory tract infection associated with a characteristic rash, which is caused by an infection with pyrogenic exotoxin (erythrogenic toxin)–producing Group A Streptococcus in individuals who do not have antitoxin antibodies. It is now encountered less commonly and is less virulent than in the past, but the incidence is cyclic, depending on the prevalence of toxin-producing strains and the immune status of the population. The modes of transmission, age distribution, and other epidemiologic features are otherwise similar to those for GAS pharyngitis.

It is characterized by:

• Sore throat
• Fever
• Bright red tongue with a "strawberry" appearance
• Characteristic rash, which:

• is fine, red, and rough-textured; it blanches upon pressure.
• appears 12–48 hours after the fever.
• generally starts on the chest, armpits, and behind the ears.
• spares the face (although some circumoral pallor is characteristic).
• is worse in the skin folds. These Pastia lines (where the rash runs together in the armpits and groin) appear and can persist after the rash is gone.
• may spread to cover the uvula.

The rash begins to fade three to four days after onset and desquamation (peeling) begins. "This phase begins with flakes peeling from the face. Peeling from the palms and around the fingers occurs about a week later. Peeling also occurs in axilla, groin, and tips of the fingers and toes


Rash:
The rash appears within 24–48 hr after onset of symptoms, although it may appear with the 1st signs of illness . It often begins around the neck and spreads over the trunk and extremities. It is a diffuse, finely papular, erythematous eruption producing a bright red discoloration of the skin, which blanches on pressure. It is often more intense along the creases of the elbows, axillae, and groin. The skin has a goose-pimple appearance and feels rough. The face is usually spared, although the cheeks may be erythematous with pallor around the mouth. After 3–4 days, the rash begins to fade and is followed by desquamation, 1st on the face, progressing downward, and often resembling that seen subsequent to a mild sunburn. Occasionally, sheetlike desquamation may occur around the free margins of the fingernails, the palms, and the soles.
Pharynx:
Examination of the pharynx of a patient with scarlet fever reveals essentially the same findings as with GAS pharyngitis.
Tongue:
In addition, the tongue is usually coated and the papillae are swollen. After desquamation, the reddened papillae are prominent, giving the tongue a strawberry appearance.


Diagnosis:
Typical scarlet fever is not difficult to diagnose; however, the milder form with equivocal pharyngeal findings can be confused with viral exanthems, Kawasaki disease, and drug eruptions. Staphylococcal infections are occasionally associated with a scarlatiniform rash. A history of recent exposure to a GAS infection is helpful. Identification of GAS in the pharynx confirms the diagnosis, if uncertain.
Treatment:
the treatment and course of scarlet fever are no different from those of any strep throat. In case of penicillin allergy, clindamycin or erythromycin can be used with success. Patients should no longer be infectious after taking antibiotics for 24 hours. People who have been exposed to scarlet fever should be watched carefully for a full week for symptoms, especially if aged 3 to young adult. It is very important to be tested (throat culture) and if positive, seek treatment.

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