Cerebral Palsy

Key points

·         Cerebral palsy (CP) refers to a nonprogressive disease of the brain originating during the prenatal, neonatal, or early postnatal period

·         Spasticity of motor movement is by far the most common presentation of CP

·         More subtle manifestations of CP include difficulties with speech, perceptive impairment, urinary incontinence, sensory loss, and difficulties with balance

·         Treatment may require multiple specialty consultation and a combined approach to therapy across several providers including oral medications, injections, and even orthopedic surgery

Background

Description

·         Cerebral palsy (CP) is a nonprogressive (static) disorder of motor function and movement that usually manifests early in life as a result of central nervous system damage to the developing brain

·         CP remains a clinical diagnosis. Evidence of motor dysfunction must be present, and clinical findings and symptoms may evolve over time. Most patients exhibit symptoms as infants or toddlers; diagnosis is often made before 2 years of age

·         Delayed motor milestones are one of the most common complaints

·         Patients with dystonia or movement disorders present later in childhood (aged older than 2 years)

·         Often associated with abnormalities of speech, vision, intellect, and (frequently) seizures

·         CP encompasses a wide spectrum of clinical presentations ranging from normal intelligence with mild motor deficits to severe retardation and inability to walk. Although there is delay in developmental motor milestones, mental retardation is seen in only 30% to 50% of patients with cerebral palsy

·         Therapy, whether for movement, speech, or activities of daily living, is the cornerstone of cerebral palsy management

·         Patients with cerebral palsy and comorbid seizure disorders should receive anti-epileptic agents suitable for the type of seizures that they experience

·         Cardinal features:

o    Hypotonia with spasticities

o    Delay in developmental milestones

o    Extrapyramidal symptoms

o    Diplegia

o    Hemiplegia

o    Seizures (30%)

o    Mental retardation (30%)

Epidemiology

Incidence and prevalence

·         1.5 to 2.5 per 1,000 live births

·         Time trends in CP are due to advances in perinatal care in the last 40 years: there was a sharp increase in prevalence of CP in very low birth weight (VLBW) infants during the 1980s, which has been attributed to the increased survival in VLBW infants due to advances in newborn intensive care. This recent increase seems to have leveled off and may be on the decline

·         Patients with mild forms of CP that do not result in severe functional impairment may remain undiagnosed, leading to underestimation of the true prevalence of CP

Demographics

Age:

·         CP is more common in children who are born very prematurely or at term

·         Swedish data indicate that 36% of patients were born at less than 28 weeks' gestation, 25% between 28 and 32 weeks' gestation, 2.5% between 32 and 38 weeks' gestation, and 37% at full term

·         Most patients are identified by 2 years of age due to delayed motor milestones

Gender:

·         There is a slightly higher prevalence in the male population, with a male:female ratio of 1.5:1.

Race:

·         There is a higher prevalence among black non-Hispanic children compared with white non-Hispanic children

Socioeconomic status:

·         Poor prenatal care may increase the incidence of cerebral palsy

·         Living in substandard housing with lead paint may increase the incidence of cerebral palsy

Causes and risk factors

·         Birth asphyxia used to be considered the principal etiology for CP. However, it is now believed that 70% to 80% of cases of CP are due to antenatal factors, while only 10% to 28% of cases are due to birth asphyxia in term and near-term infants

·         More than 1 etiologic factor is often identified. For example, intrauterine infection may result in growth restriction, maternal fever, and prematurity, all of which have been associated with CP

Prenatal causes:

·         Abnormal intrauterine growth may be the result of multiple factors such as placental insufficiency, intrauterine infection, and chromosomal abnormalities, among others

·         Maternal infections and fever: evidence of maternal fever around the time of delivery and chorioamnionitis have been associated with low Apgar scores, neonatal encephalopathy, seizures, and increased risk of CP

o    TORCH infections (toxoplasmosis, syphilis, rubella, cytomegalovirus, varicella zoster, HIV, herpes viruses) are thought to be responsible for 5% of CP cases

·         Multiple births: twins carry a higher risk of CP when compared to single births; risk of having a child with CP is 0.2% for single births, 1.3% for twins, and 7.6% for triplets

o    Weight discordance greater than 30% is associated with a 5-fold increased risk of CP

o    Death of a co-twin or co-triplet is associated with a 10% and 29% risk of CP for the surviving twin or triplets, respectively

·         Placental pathology:

o    Thrombotic lesions and placental ischemia have been associated with spastic diplegia

o    Chronic villitis (focal areas of inflammation) has been associated with growth restriction, preterm birth and pre-eclampsia

·         Genetic factors

·         Maternal metabolic disturbances (diabetes mellitus type 1 or type 2 or thyroid abnormalities)

·         Intrauterine exposure to toxins

·         Malformations of cortical development

Perinatal causes:

·         Hypoxia-ischemia: 6% of children with CP have an identifiable birth complication that could result in hypoxia. Neonatal encephalopathy is usually present

·         Periventricular leukomalacia (PVL) increases the risk of CP, independent of gestational age. Approximately 75% of infants with cystic PVL develop CP

·         Fetal/neonatal stroke: most often resulting in hemiplegic CP

·         Hyperbilirubinemia

o    Hemolytic disease in the newborn, especially due to Rh incompatibility, was previously a common cause of kernicterus and CP prior to the use of Rho(D) immune globulin. It is still being reported in North America, Western Europe and the developing world

o    Kernicterus is the preferred term to describe the chronic permanent sequelae of bilirubin toxicity. Affected children often develop severe athetoid CP

Postnatal causes:

·         Stroke

·         Trauma

·         Infection

Associated disorders

·         Seizures

·         Scoliosis

·         Deafness

·         Mental retardation

·         Visual impairments: strabismus, nystagmus, optic atrophy

·         Speech deficits

·         Feeding difficulties

·         Urinary incontinence

·         Attention deficit hyperactivity disorder

·         Learning disabilities

·         Depression

·         Autism

Screening

Not applicable.

Primary prevention

Summary approach

·         Since the cause of cerebral palsy is not always known, it is difficult to prevent; however, some prenatal causes can be prevented with appropriate prenatal care

o    The risks associated with preterm delivery may be minimized with early and regular prenatal physician visits

o    The use of antenatal corticosteroids (ie, betamethasone) in patients at risk for pre-term delivery seems to reduce the risk of CP by protecting against neonatal intraventricular hemorrhage (IVH)

o    Prophylactic magnesium sulfate was administered to women for whom preterm delivery was imminent in the Beneficial Effect of Antenatal Magnesium (BEAM) trial to assess reduction in the risk of death or moderate to severe cerebral palsy in their children. The results suggested that although the risk of death or moderate to severe CP did not seem to decrease, the overall rate of CP was reduced among child survivors

·         Head injuries can be prevented by proper positioning in car seats

·         Routine vaccinations in infants can prevent many cases of meningitis that leads to brain injury

Preventive measures

·         Administering prophylactic magnesium sulfate to women for whom preterm delivery is imminent may reduce the incidence of CP

·         Pregnant women should be advised not to smoke because it increases the risk of prematurity. Smoking also damages the placenta and can contribute to neonatal hypoxia and brain damage, which increases the risk of cerebral palsy

·         Pregnant women should be advised not to drink alcohol or take unprescribed drugs because of risk of neural tube damage to the baby. Early brain damage during development in utero can lead to cerebral palsy

·         Pregnant women should avoid eating raw shellfish and soft cheeses

·         Pregnant women should avoid all unnecessary X-ray radiation because it may damage developing neural tissue, which can increase the risk of developing cerebral palsy

·         Exposure to toxins should be avoided, such as ingestion or inhalation of lead paint

·         Ensure that any high-risk delivery occurs in a center where any complications can be managed (eg, cesarean section for prolonged labor, fetal distress, or dystocia)

·         If a preterm delivery is imminent, ensure that the adequate staff and facilities are available to manage the neonate and prevent hypoxia and acidosis after delivery. Low birth weight infants are at increased risk of developing cerebral palsy from intracerebral hemorrhage and periventricular leukomalacia. Prematurity is the most common natal cause of cerebral palsy

·         Infants should receive Haemophilus influenzae type b and pneumococcal vaccines to protect against meningitis

·         Rh-negative women should receive Rho(D) immune globulin to prevent destruction of fetal blood cells

·         Pregnant women should be assessed for immunity to rubella. Rubella infections during pregnancy can damage the developing brain

·         Ensure that any diabetic woman has good glycemic control when pregnant to decrease the risk of developmental problems in the fetus

·         Minimize intrauterine exposure to maternal infection

Evidence

·         A systematic review assessed the effects of magnesium sulfate as a neuroprotective agent when given to women considered at risk of preterm birth in 5 RCTs inclusive of 6,145 neonates. Women presenting from 24.0 to 31.6 weeks' gestation with advanced preterm labor or premature rupture of the membranes and no recent exposure to magnesium sulfate were randomized to receive either intravenous magnesium sulfate or masked study drug placebo. If after 12 hours delivery had not occurred and was not anticipated, the infusion was stopped. Patients were assessed for signs of intolerance to the study medications and maternal data were collected up to hospital discharge. Up to 3 follow-up visits were scheduled over 2 years where certified examiners, masked to study group assignment, collected physical and neurological data, including a modified Gross Motor Function Classification Scale. The Bayley Scale of Infant Development was also administered. Antenatal magnesium sulfate reduced the risk of cerebral palsy. There was also a significant reduction in the rate of substantial gross motor dysfunction. Overall there were no significant effects of antenatal magnesium therapy on combined rates of mortality with cerebral palsy. There were higher rates of minor maternal side effects in the magnesium groups, but no significant effects on major maternal complications.[1]Level of evidence: 1

Celiac Disease

Celiac Disease

Key points

·         Celiac disease is an immune-mediated enteropathy that results from increased sensitivity to and intolerance of gluten proteins. The immunologic reaction to gluten proteins promotes injury to the intestinal mucosa, resulting in diarrhea, steatorrhea, bloating, flatulence, and fatigue in adults. In children, the condition presents as irritability and failure to thrive. Enteropathy is its most common presentation, though celiac disease can affect other organ systems

·         Celiac disease is genetically transmitted and affects 0.5% to 1% of the people in the western hemisphere and Europe

·         Presence of class II human leukocyte antigen DQ2 and DQ8 confers an increased risk of developing celiac disease

·         Serologic detection of immunoglobulin A (IgA) anti-endomysial antibodies during a gluten–non-deprived diet is a useful screening test in suspected individuals

·         The sine qua non of diagnosis in celiac disease is small intestinal biopsy obtained during a gluten–non-deprived diet

·         A gluten-free diet is the mainstay of treatment

Background

Description

·         Celiac disease is a lifelong intolerance to gluten, causing autoimmune injury to the mucosa of the upper small intestine. Damaged intestinal epithelium subsequently impairs digestion and absorption of nutrients, producing the clinical signs and symptoms of the disease

·         The condition may be classified as asymptomatic, classic, and atypical:

o    Asymptomatic patients present with no clinical disease manifestations

o    Classic presentation symptoms include diarrhea, steatorrhea, bloating, flatulence, and ensuing nutrient and mineral deficiencies.

o    Atypical patients present with predominantly extraintestinal manifestations with absent or minimal gastrointestinal manifestations. Extraintestinal manifestations include anemia, dermatitis herpetiformis, aphthous stomatitis, neurologic dysfunction, osteopathy, and diabetes mellitus

·         Synonyms include gluten-sensitive enteropathy and nontropical sprue

Epidemiology

·         Celiac disease affects 0.5% to 1% of the population

·         Its prevalence is decreased among blacks and those of Hispanic or Asian ethnicity

·         The incidence of symptomatic celiac disease in adults is estimated at 2 to 13 per 100,000 per year

Causes and risk factors

·         Gliadins and glutenins in the presence of CD4+ T cells with HLA-DQ2 and HLA-DQ8 activate cytokine production and clonal expansion of antibody-producing B cells, which lead to lymphocyte-mediated destruction of the epithelium and mucosa. This is termed the adaptive response. The resulting injury impairs villous function and absorption of nutrients, producing the clinical signs and symptoms of celiac disease. In addition, there is an innate response, which involves interleukin-15 expressed by enterocytes

·         Celiac disease affects predominantly the mucosa of the proximal small intestine, which receives the majority of dietary gluten. Distal parts of the small intestine are less affected because gluten has generally been absorbed by the time the enteric bolus reaches these areas

Risk factors

Geographic:

·         The highest incidence of celiac disease is found in western Europe and the U.S.

Age:

·         Peaks in diagnosis occur in childhood (when approximately 6% of the cases are diagnosed) and between the fifth and seventh decades of life

Female gender:

·         The female-to-male ratio in celiac disease is about 2:1

Heredity:

·         Celiac disease is an inherited condition with a concordance rate of 70% to 100% between monozygotic twins

·         The concordance rate among siblings is 7% to 30%. The rate increases up to 40% if the sibling has the same HLA risk haplotype as the index case

·         Risk is higher among first-degree relatives of those with the condition, with a 1:22 ratio, compared with the risk among second-degree relatives (1:29)

·         At lease 11% of first-degree relatives of index cases have celiac disease

Infant diet:

·         If gluten-containing foods are brought into the diet within the first 3 months or after 7 months of life, the risk of developing celiac disease increases five-fold

·         The risk is higher in the first 3 months because of the infant's underdeveloped intestinal mucosal barrier, which allows immunogenic peptides to cross the epithelium

Absent breastfeeding:

·         Breastfeeding protects against the development of celiac disease in childhood. Gradual introduction of gluten-containing foods while breastfeeding decreases the risk by 48%. Its benefit in preventing the disease later in adulthood, however, is unknown

·         Breastfeeding may have the following protective effects:

o    Continuation of breastfeeding limits the amount of gluten a child receives

o    Breast milk protects against gastrointestinal infections that increase the permeability of the intestinal mucosa to gluten

o    IgA in breast milk agglutinates with antigen, preventing the antigen's uptake to the mucosa

o    Breast milk has T-cell–specific suppressive effects

Inflammatory bowel disease:

·         A few studies have shown an increased prevalence of celiac disease in patients with Crohn disease and, to a lesser extent, ulcerative colitis

Comorbid risk factors:

·         Lymphocytic colitis (increases risk of celiac disease 15%-27%)

·         Down syndrome (increases risk 12%)

·         Type 1 diabetes mellitus (increases risk 5%-6%)

·         Autoimmune thyroid disease (increases risk 5%)

·         Chronic fatigue syndrome (increases risk 2%)

Screening

Summary approach

Screening for celiac disease is essential to avoid unnecessary loss of growth potential in children at risk for the disease (eg, those children with a family history) and untreated progression of disease or complications in adults similarly at risk (eg, those with autoimmune disease). In these instances, testing for the disease even in asymptomatic patients should be strongly considered.

Population at risk

·         Screening for celiac disease is recommended for individuals with certain autoimmune and comorbid disorders (eg, lymphocytic colitis, Down syndrome, type 1 diabetes mellitus, autoimmune thyroid disease, and chronic fatigue syndrome) who are at increased risk for celiac disease. Screening is also recommended for first-degree relatives of patients with celiac disease. Screening of the general population for celiac disease is not recommended

·         Screening for celiac disease is also advised for patients with the following conditions:

o    Unexplained iron-deficiency anemia

o    Early-onset or unexplained osteopenia or osteoporosis

o    Unexplained elevated hepatic transaminases

o    Dermatitis herpetiformis

o    Unexplained epilepsy

o    Failure to thrive, developmental delay, growth retardation, and other unexplained nutritional problems (pediatric patients)

o    Poor glucose control, lactose intolerance, diarrhea, and bloating (diabetic patients)

o    Recurrent pancreatitis and no clear etiology

o    Unexplained infertility, recurrent spontaneous abortion, stillbirth, perinatal death, and intrauterine growth retardation in women

o    Unexplained chronic diarrhea

Evidence

·         According to a population-based cohort study of 111 index cases and their family members from southeast Minnesota, the prevalence of celiac disease in family members was estimated to be 11%. All affected family members carried the at-risk HLA-DQ genotype. Occult intestinal villous atrophy was present in more than half of the cases. High risk factors for celiac disease include carrying HLA-DQ2 (OR = 16.1) and being a sibling (OR = 2.5).[1]Level of evidence: 3

·         A multicenter, prospective study was conducted from 2002 to 2004 on 976 adult subjects who attended a participating primary care practice. Those with symptoms or conditions known to be associated with celiac disease were tested. Of these, 30 (3.07%) had a positive anti-tTG test, and celiac disease was diagnosed in 22 patients (18 women). Prevalence of celiac disease in the serologically screened sample was 2.25%. Diagnostic rate was 0.27 cases/1000 visits at baseline and 11.6/1000 after active screening.[2]Level of evidence: 3

References

Screening modalities

·         Serologic testing for the detection of IgA antiendomysial antibodies is the preferred method of screening for individuals suspected of having celiac disease because it has high sensitivity and specificity (approaching 100%)

·         A total serum IgA level is preferred as patients deficient in IgA may be unable to produce the antibodies on which further screening tests depend

Prevention

Summary approach

Celiac disease in susceptible individuals can only be successfully prevented by strict avoidance of all gluten-containing foods.

Population at risk

Infants with a family history of celiac disease are at increased risk and may benefit from delayed introduction of gluten in the diet and prolonged breastfeeding.

Preventive measures

·         Introduction of gluten-containing food within the first 3 months of life increases the risk of celiac disease. At the time of weaning, gluten-containing food products should not be introduced in large amounts

·         Breastfeeding is encouraged to decrease the risk of celiac disease; however, the optimum duration of breastfeeding is not known