Pediatric 3 Flashcards

Question

Neonatal hypoglycaemia Definition Physiology Cf Causes Ttt Neonatal hypoglycaemia (vs.) NEONATAL HYPOCALCEMIA

Answer 1

It is defined as blood glucose level <1.4mmol/L(25mg/dl)in the first 24 hours of life and< 2mmol/L(40mg/dl) thereafter. 90% of glucoseis consumed by the brain. Blood glucose is maintained by: 1. Adequate fetal glycogen stores. 2. Effective glycogenolysis and gluconeogenesis. 3. Good intake. Clinical Features: Tachycardia, jitteriness, lethargy, poor feeding, apnea, cyanosis, seizure. Some cases are asymptomatic & treated by early feeding. Causes of Neonatal Hypoglycemia: 1. I.U.G.R. 2. Prematurity. 3. Birth asphyxia. 4. Neonatal sepsis. 5. Delayed or poor feeding. 6. IDM(infants of diabetic mothers). TREATMENT OF HYPOGLYCEMIA: 10%Dextrose i.v.as 4ml/kg stat, then 8mg/kg/minute is given if blood glucose is <25mg/dl. If blood glucose remains low for more than 7days (persistent hypoglycemia): increase the dose of dextrose to 16-20mg/kg/minute, and investigate for causes e.g. hyperinsulinism & inborn error of metabolism. NEONATAL HYPOCALCEMIA: Calcium is present in three forms: 1. Protein bound (40%). 2. Bound to citrate or phosphate (10%). 3. Ionized: which is the active part (50%). Hypocalcemia is defined as: serum calcium < 2 mmol/L (8 mgdL) in term, or less than 1.75 mmol/L (7 mg/dL) in preterm neonates, or ionized calcium < 4mgdL Acidosis results in an increased ionized calcium and alkalosis decreases it. SCREENING FOR HYPOCALCEMIA IS ROUTINELY INDICATED IN: 1. Preterm neonates. 2.I.D.M. 3. Severe perinatal asphyxia. CLINICAL FEATURES: range from asymptomatic to jitteriness, tremor of the extremities, tetany, cardiac arrhythmias, convulsions, apnea, and stridor. TYPES OF NEONATAL HYPOCALCEMIA: 1. Early: which presents within the first 72 hours, due to poor feeding e.g. in RDS, preterm, sepsis. 2. Late which presents at 5-7days up to several weeks,due to transient hypoparathyroidism, or high phosphorus content in milk. TREATMENT: If convulsions are present give 10% calcium gluconate 100-200mg/kg by i.v. infusion (0.2-0.5ml/kg) for three days. Always watch for extravasation & tissuing of calcium which may cause skin necrosis. Oral vit.D 5000 1.U./day should also be given.

Answer 2

INFANTS OF DIABETIC MOTHERS (IDM): Infants born to type 1 or 2 or gestational diabetic mothers have higher mortality rates, and most of them are L.G.A., but they may be growth restricted if DM is complicated by vascular disease or if they are delivered before term. PATHOHPYSIOLOGY: Maternal hyperglycemia causes fetal hyperglycemia and fetal hyperinsulinemia. The resultant fetal increased hepatic glucose intake and lipogenesis causes hypertrophy and hyperplasia of pancreatic islet cells and all fetal organs (except the brain), and extramedullary hematopoiesis. Separation of the placenta at birth suddenly interrupts glucose infusion to the neonate, and hypoglycemia develops in the first few hours after birth. CLINICAL MANIFESTATIONS: Most IDM are large and plump (due to increased body fat and enlarged viscera). They have higher risk for birth trauma and congenital anomalies, with puffy, plethoric facies. Hypoglycemia develops in 25-50% of IDM, but only a small percent of them become symptomatic in the first 3 days of life; similar signs can be due to hypocalcemia and asphyxia. IDM have a higher incidence of T.T.N., R.D.S., N.N.J., hypothermia, polycythemia, and renal vein thrombosis. Congenital heart disease, asymmetrical septal hypertrophy, cardiomegaly, and heart failure are more common in IDM. TREATMENT OF IDM: 1.Good glycemic control before and during pregnancy can reduce mortality and complications of IDM. 2.IDM should start feedings within 1 hr. after birth with close observation. 3.Treatment is indicated if the infant is symptomatic and plasma glucose < 40mg/dl, or asymptomatic and plasma glucose is < 30mg/dl. 4.Treatment of RDS, hypocalcemia, hypomagnesemia, and polycythemia. PROGNOSIS OF I.D.M.: •They have a higher incidence of subsequent DM and childhood obesity that may extend to adult life.

Answer 3

NEONATAL ASPIRATION PNEUMONIAS 1. MECONIUM ASPIRATION: Meconium-stained amniotic fluid is found in 10-15% of births (usually term or postterm),following fetal distress & hypoxia. 5% of such infants develop meconiumaspiration pneumonia when thick meconium is aspirated into the lungs while in utero or with the first breath. 1. Plugging of small airways with hyperinflatio TREATMENT: 1. Supportive care and physiotherapy. 2. I.P.P.V. 3. Surfactant therapy. 4. Inhaled nitrous oxide (iNO). 5. E.C.M.O.(extracorporeal membrane oxygenation). 6. Pulmonary hypertension may follow, and a non selective pulmonary vessel alpha blocker tolazoline is used. 7. Antibiotics. 8. Pneumothorax occurs in 15% of cases, it should be treated accordingly. 2. MILK ASPIRATION: Commonly occurs in preterm infants, or in full term infants with improper feeding technique. It is characterized by sudden deterioration in clinical condition (apnea or severe distress). CXR shows pneumonic patch or collapse usually involving the right upper lobe. TREATMENT: Supportive care.

Answer 4

NORMAL LUNG FUNCTION REQUIRES: 1.Clearance of fetal lung fluid. 2.Establishment of spontaneous breathing. 3.Release of surfactant. 4.Decreasein pulmonary vascular resistance. 5.Cessation of right to left shunting of venous blood returning to the heart. Interference with any of these mechanisms will result in respiratory distress in the neonate. T.T.N. and R.ID.S. are the commonest causes for respiratory distress in neonates at all. TRANSIENT TACHYPNEA OF THE NEWBOMF (T.T.N.) Is defined as tachypnea of a newborn(commonly affects term babies) without prominent respiratory distress signs, occurring shortly after birth, due to delayed resorption of lung fluid, with rapid resolution by 24-72 hours in most cases. PREDISPOSING FACTORS OF T.T.N.: 1. C.S. 2. Perinatal asphyxia. 3. Hypothermia. 4. Maternal DM and asthma. 5. Large baby. C.X.R.: a. Hyperinflation. b. Peri-hilar opacities. c. Fluid in the transverse fissure (appears as white streaks in lung fissures which disappears within few days) MANAGEMENT • Oxygen for 2-3 days, concentration more than 40% is rarely needed. • Antibiotics, since it initially may simulate G.B.S. pneumonia. • Diuretics are not useful. RESPIRATORY DISTRESS SYNDROME (R.D.S) : Preterm infants have pulmonary immaturity which results in surfactant deficiency. Surfactant (produced by type 2 pneumocytes) is a complex mixture of phospholipids, proteins, And lipids that lowers the surface tension of the alveolar membrane. Without surfactant the alveoli w ill collapse at the end of each expiration? and this can lead to K.D.S. and respiratory failure in the neonate. The risk of R.D.S. is inversely correlated with gestational age. Nearly all infants born before 28 weeks of pregnancy develop R.D.S. RISK FACTORS FOR R.D.S. INCLUDE: 1. Previous sibling with R.D.S. 2. Maternal D.M. 3. Cesarean section(C.S.). 4. Rapid labor. 5. Multiple pregnancy. THE INCIDENCE OF R.D.S. IS DECREASED WITH: 1. Use of antenatal steroids. 2. Maternal hypertension. 3. Prolonged rupture of membranes. The synthesis of surfactant requires normal temperature, normal PH, and normal lung perfusion. Phosphatidyl choline (Lecithin) is the major constituent of the mature surfactant. Lecithin to sphyngomyelin (L/S) ratio (measured in a sample of amniotic fluid collected via amniocentesis) is a standard test to confirm R.D.S. Lecithin and sphyngomyelin are phospholipids found in the amniotic fluid. As the lung matures and begins to produce surfactant; Lecithin levels will increase, while sphingomyelin level remains constant. L/S ratio of 2.0 or greater indicates that R.D.S. is unlikely because there is enough surfactant. SURFACTANT DEFICIENCY LEADS TO: a. Alveolar collapse and hypoventilation with CO2 retention. b. Reduced lung volume and compliance with increased dead space. c. Ventilation / perfusion mismatch. d. Pulmonary hypertension. e. Right to left (R-L) shunt. NATURAL HISTORY OF RDS: It appears immediately or within the first 4 hours after birth, then it worsens for the next 48-72 hours. Clinical recovery coincides with the onset of diuresis after a period of oliguria, and resolution occurs 2-4 days later, but some neonates may remain O2 dependent for several weeks. CLINICAL PRESENTATION OF R.D.S.: 1. Tachypnea (respiratory rate > 60/min.). 2. Grunting. 3. Sternal, intercostal, and subcostal retractions. 4. Cyanosis in room air. 5. Oliguria. 6. Mixed respiratory and metabolic acidosis. Grunting: is a short, low pitched sound heard when the infant expires with a partially closed glottis. It can conserve lung volume and keep the alveoli opened. Grunting indicates a parenchymal disease and poor lung compliance. C.X.R. : Typical findings appear at 6-12 hr.: 1. Diffuse bilateral reticulo-granular infiltrates (ground glass appearance) with small lung volume and a bell-shaped thorax. 2. Air bronchogram . 3. In severe cases there is complete white-out of lung fields. Air bronchogram refers to the phenomenon of air-filled bronchi (dark) being made visible by the opacification of surrounding alveoli (grey/white). It is almost always caused by a pathologic airspace/alveolar process, in which something other than air fills the alveoli. Air bronchograms will not be visible if the bronchi themselves are opacified (e.g. by fluid) and thus indicate patent proximal airways. PREVENTION OF R.D.S.: a. Good antenatal care. b. Good selection and timing of C.S. (avoid doing elective C.S. for low risk fetuses before 39 wk. of gestation, because surfactant secretion generally increases during labor). c. Antenatal steroid. d. Surfactant replacement (surfactant can be used as prophylaxis and as rescue treatment for R.D.S.). ANTENATAL STEROIDS: When given to mothers suspected to get preterm delivery (at 24-34 wk.) 1-2 days before delivery can induce fetal surfactant production. Betamethasone (2 i.m. doses) is superior to Dexamethasone (4 i.m. or i.v. doses) which can cause periventricular leukomalacia in the newborn baby. SURFACTANT REPLACEMENT : Given within 20-30 minutes after birth by trained physicians in qualified centers (3-4 ml/kg as 2 doses 12 hours apart) via endotracheal tube. Surfactant reduces the incidence and severity of major complications of prematurity (R.D.S., I.V.H., N.E.C., P.D.A., B.P.D.), and also reduces the need for MECHANICAL VENTILATION & NEONATAL MORTALITY. TYPES OF SURFACTANT: a. Natural (bovine or porcine) is preferred. b. Synthetic. COMPLICATIONS OF SURFACTANT: 1. Blockage of endotracheal tube. 2. Hypoxia(transient). 3.Hypotension. TREATMENT OF R.D.S. (IN THE N.I.C.U.): a. Maintain temp. at 36.5-37.5 at all times. b. Correct hypoxia by O2 ( 85-93% ) or assisted ventilation. c. Correct acid - base abnormalities . d. Nutrition (20ml/kg/day of breast milk), T.P.N. e. Antibiotic (Ampicillin & Gentamicin) because it is difficult to differentiate R.D.S. from G.B.S. pneumonia. f. Inhaled nitrous oxide which improves gas exchange. g. i.v. fluid (10%dextrose)70ml/Kg/day. h. Management of P.D.A. Causes of sudden deterioration of r.d.s. while on spontaneous breathing: 1. Pneumothorax. 2. Periventricular hemorrhage. 3. Aspiration. 4. Apnea. 5. Infection. COMPLICATIONS OF R.D.S.: 1. Air leak . 2. P.D.A . 3. Periventricular hemorrhage . 4. Pneumonia . 5. Complications of mechanical ventilation. 6. Long term sequelae e.g. R.O.P. & B.P.D. (which occur in severe cases of R.D.S. which require assisted ventilation for > 4 weeks). BRONCHOPULMONARY DYSPLASIA Chronic respiratory distress following prolonged exposure (>28 days) to high pressure LP.P.V. causing repeated over- distension of the alveoli & alveolar ducts in neonates with pulmonary insufficiency (usually preterm). CXR in B.P.D. shows massive destruction of lung tissues, with areas of collapse, atelactasis, and cystic

Answer 5

NEONATAL APNEA: • Definition: • Cessation of breathing for > 20 seconds, or for any duration if associated with bradycardia or cyanosis. • Periodic breathing : • Series of respiratory pauses of 10 seconds occuring at least 3 times/minute, followed by a series of rapid, shallow breaths without bradycardia or cyanosis. It is common in premature neonates. TYPES OF APNEA: • Central : due to cessation of motor stimuli from the brain stem. Chest wall motions are absent. • Obstructive : absence of airflow, with aggressive chest wall motion. • Mixed : is the commonest type. CAUSES OF APNEA: • Hypoxia. • Sepsis. • Metabolic disorders. • CNS disorders. • Circulatory e.g. hypotension, heart failure, anemia, polycythemia. • Hyperthermia, Hypothermia. • Excessive pharyngeal suctioning. • Over dose of anticonvulsants e.g. Diazepam, Phenobarbiton. • Apnea of prematurity. So the diagnosis of apnea requires investigations of the above causes by appropriate tests. • 1. Apnea monitors. TREATMENT : • 2. Repeated stimulation. • 3. Intermittent bag&mask. • 4. C.P.A.P.(CONTINOUS POSITIVE AIRWAYS PRESSURE)VENTILATION is useful in cases of obstructive and mixed apnea, but not useful in central apnea. • 5. Drugs e.g. Theophylline (5-7mg/kg loading, then 12mg/kg/6-12hr.oral or i.v.) It is useful in all types of apnea. It sensitizes the respiratory centers to hypercapnia & it stimulates the diaphragm, but it decreases cerebral blood flow. • Other drugs e.g. Caffaine citrate and Doxapram. APNEA OF PREMATURITY: • Immaturity of respiratory centers or chemoreceptors in premature babies may cause irregular stimulation of breathing and recurrent apnea. CENTRAL RECEPTORS respond to hypercapnia and acidosis. CHEMORECEPTORS (carotid and aortic bodies) respond to hypoxia.

Answer 6

PERINATAL ASPHYXIA: Perinatal asphyxia occurs when antepartum, intrapartum, neonatal, or a combination of these events result in hypoxia and ischemia of the brain (the so-called hypoxic- ischemic encephalopathy) and other organs. HYPOXIC-ISCHEMIC ENCEPHALOPATHY(H.I.E.): Hypoxia means decreased arterial concentration of oxygen. Ischemia means blood flow to cells or organs that is insufficient to maintain their function. H.I.E. is an important cause of permanent damage to C.N.S. tissues that may result in neonatal death, or manifest later as cerebral palsy (C.P.) or developmental delay. CRITERIA OF PERINATAL ASPHYXIA: 1. Umbilical cord arterial PH < 7. 2. APGAR score of 0-3 for > 5 minutes. 3. Neonatal neurological manifestations (convulsions, coma, hypotonia). 4. Multisystem organ dysfunction. RISK FACTORS IN THE NEONATE FOR H.I.E. : 1. Very low APGAR score. 2. Acidotic infants. 3. Those who require C.P.R. (cardiopulmonary resuscitation). APGAR score is done at 1 minute after birth. It consists of 5 criteria, each one of these criteria is graded as zero, 1, or 2 with a total score of 10 RISK FACTORS IN THE MOTHER FOR H.I.E.: Before delivery : eclampsia, uterine infections, bleeding, severe anemia. During labor : premature labor or prolonged labor, malpresentation, general anesthesia(G.A.). CAUSES OF LOW APGAR SCORE: 1. Fetal asphyxia. 2. Maternal G.A. or sedation with morphine or pethidine within the last 4 hours before delivery. 3. L.B.W. & prematurity. 4. Difficult or traumatic delivery. RESULTS and INTERVENTIONS at 1 min. SCORE: 7or > 7 (normal) : No resuscitation. 5-6 (moderate asphyxia) : Bag and mask. 4 or < 4 (severe asphyxia) : Endotracheal intubation and assisted ventilation. Low score should be repeated at 5 ACUTE SEQUALAE OF ASPHYXIA : 1. Cerebral hypoxia. 2. Convulsions. 3. I.V.H. 4. Renal failure. 5. Anoxic cardiomyopathy. 6.N.E.C. 7.Metabolic(hypoglycemia, hypocalcemia, inappropriate A.D.H. secretion). LONG-TERM OUTCOMES AFTER H.I.E. : 1. Cognition and developmental delay. 2. Learning difficulties. 3. Cerebral palsy. 4. Vision defects. 5. Epilepsy. 6. Hearing loss. TREATMENT OF PERINATAL ASPHYXIA: 1.Treatment of cerebral edema: a. Correct hypoxia & acidosis. b. Control convulsions (in 20-50% of HIE cases). c. Restrict i.v. fluid to 60 ml/kg/day. d. Mannitol 5 ml/kg/dose over 20 minutes, can be repeated 4 times a day. e. Dexamethason 1 mg loading dose then 0.3 mg/kg 8 hourly for 3 days. f. Hyperventilation. 2. Maintain normal cerebral tissue perfusion e.g.by giving blood to prevent neuronal damage. 3. Maintain renal function

Answer 7

TOXOPLASMOSIS: Toxoplasma gondii is an obligate intracellular parasite that can infect humans through the feces of its primary host which is the cat. Congenital toxoplasmosis results from vertical (transplacental) transmission of the parasite from an acutely infected mother to her fetus. If infection occurs early in pregnancy, there is low rate of transmission, but it causes severe disease, while infection late in pregnancy causes high transmission, but more benign symptoms. Clinical features: The classic findings of S.G.A., microcephaly, hydrocephalus, chorio-retinitis, and intra-cerebral calcifications. Jaundice, hepatosplenomegaly(HSM). Generalized maculopapular rash. Seizures. Long-term neurologic & developmental complications. Diagnosis: IgG-specific antibodies achieve a peak concentration 1-2 months after infection and remain positive indefinitely. Specific IgM antibody determinations should be performed to confirm disease. Treatment: Pyrimethamine (supplemented with folic acid) combined with Sulfadiazine should be given both for symptomatic and asymptomatic congenital infections for up to 1 year.

Answer 8

RUBELLA: If infection is acquired during the first 4 weeks of gestation; most newborns will have congenital defects. Infection acquired after 4 months' gestation does not seem to cause disease. Clinical features: Classical triad of cataract, cardiac defects(PDA), and deafness (sensorineural). Meningoencephalitis, Mental retardation. Jaundice, HSM, post auricular lymphadenopathy. Thrombocytopenia. Radiolucent bone disease. Purpuric skin lesions "blueberry muffin" appearance resulting from extramedullary (dermal) erythropoiesis. Diagnosis: -Detection of rubella-specific IgM antibody in the infant usually indicates recent infection. -Rubella virus can be isolated from blood, urine, CSF, and throat swab specimens. -Infants should be isolated while in hospital, and kept away from susceptible pregnant women when sent home. -No treatment is available for congenital rubella syndrome.

Answer 9

CYTOMEGALOVIRUS: CMV is the most common congenital infection, and is the leading cause of sensorineural hearing loss, mental retardation, retinal disease, and cerebral palsy. The earlier in gestation that the primary maternal infection occurs, the more symptomatic the infant will be at birth. CMV infection acquired during birth or from mother's milk is not associated with newborn illness or CNS sequelae. Clinical features: Microcephaly. Thrombocytopenia. HSM. Chorio-retinitis. Hearing abnormalities. A blueberry muffin appearance as the result of dermal erythropoiesis. Skull films may reveal periventricular calcifications. Diagnosis: -Detection of the virus in urine or saliva of the infant. -PCR can detect small amounts of CMV DNA in urine. -Detection of CMV within the first 3 weeks after birth is considered as a proof of congenital CMV infection. Treatment: -No antiviral agents currently approved for the treatment of congenital CMV infection. -Ganciclovir and Valganciclovir can only delay the progression of hearing loss.

Answer 10

HERPES SIMPLEX VIRUS: HSV type 2 is responsible for most cases of primary (maternal) genital herpes & neonatal herpes simplex infection. Neonatal infection is acquired from the mother shortly before or during passage through the birth canal at delivery. Infants with HSV infections are more likely to be born prematurely. Clinical features Most infants are normal at birth, and symptoms of infection develop at 5-10 days of life either as: disseminated disease involving multiple organ systems, especially the liver and lungs, or as localized infection to the CNS, skin, eyes, and mouth. HSV infection should be suspected in any neonate with fever, irritability, seizures, and abnormal CSF findings. HSV infections are often severe, and a delay in treatment results in significant morbidity & mortality. Diagnosis: - Specimens for viral culture (blood, urine, saliva). - PCR is a sensitive method for detecting HSV DNA in blood, urine, and CSF. Treatment: Parenteral Acyclovir is the treatment of choice for neonatal HSV infections.

Answer 11

CONGENITAL SYPHILIS: It commonly results from transplacental infection with the Gram negative spirochet Treponema pallidum to the fetus. Syphilis during pregnancy has about 100% transmission rate. -Intrauterine infection can result in stillbirth, non immune hydrops fetalis, or prematurity. -Early manifestations: -Snuffles (syphilitic rhinitis) is the first symptom seen in up to 50% of newborns with congenital syphilis. -HSM, LAP. -Severe pneumonia and osteochondritis. -A maculopapular desequamative rash develops over the palms and soles and around the mouth and anus. -Hemolytic anemia and thrombocytopenia. -Late manifestations: -Interstitial keratitis. -Deafness. -Frontal bossing. -Saddle nose. -Hutchinson teeth (triangular or peg like appearance of the incisors and molars). -Mulberry molars (physically defective permanent molars). -Bowing of the shins. -Clutton joints (symmetrical hydrarthrosis of knee joints). TREATMENT: Parenteral penicillin G (for 10 to 14 days) is the drug of choice for treatment of syphilis.

Answer 12

Autosomal Dominant Inheritance - is determined by the presence of 1 abnormal gene on 1 of the autosomes (chromosomes 1-22). - In an autosomal dominant trait, a change in 1 of the paired genes has an effect on the phenotype. - The disorder is transmitted in a vertical (parent-to-child) pattern and can appear in multiple generations. - An affected individual has a 50% (1 in 2) chance of passing on the deleterious gene in each pregnancy and, therefore, of having a child affected by the disorder. This is referred to as the recurrence risk for the disorder. - Unaffected individuals (family members who do not manifest the trait) do not pass the disorder to their children. - Males and females are equally affected. - Although parent-to-child transmission is a characteristic of autosomal dominant inheritance, for many patients with an autosomal dominant disorder there is no history of an affected family member. There are several possible reasons: 1. New mutation 2. Incomplete penetrance, meaning that not all individuals who carry the mutation have phenotypic manifestations. 3. Variable expression: Individuals with the same autosomal dominant mutation can manifest the disorder to different degrees. 4. Somatic mutations: Some spontaneous genetic mutations occur not in the egg or sperm that forms a child, but rather in a cell in the developing embryo. 5 . Germline mosaicism: the mutation occurs in cells that populate the germline that produce eggs or sperm. Examples of AD disease: achondroplasia, hereditary spherocytosis, neurofibromatosis, Marfan syndrome, and osteogenesis imperfecta.

Answer 13

Autosomal Recessive Inheritance - Horizontal transmission, the observation of multiple affected members of a kindred in the same generation, but no affected family members in other generations. - Recurrence risk of 25% for parents with a previous affected child. - Males and females being equally affected. - The affected individual should be homozygous for the affected gene. - If both parents are heterozygous the chance of having affected child is 25%. - If the affected person married from normal person, all the children will be heterozygous. - If affected person married from a heterozygous person the children will be:  50% affected. It is called Pseudodominant inheritance, which refers to the observation of apparent dominant (parent to child) transmission of a known AR disorder. 50% heterozygous (carrier). Examples of AR disease: Sickle cell disease, PKU, Tay-sachs disease, Cystic Fibrosis, Hurler Disease, Werdnig-Hoffmann Disease, Alkaptonuria, Albinism, and Congenital adrenal hyperplasia.

Answer 14

X-Linked Recessive Inheritance ◆ Males are more commonly and more severely affected than females. ◆ Female carriers are generally unaffected. ◆ Female carriers have a 25% risk for having an affected son, a 25% risk for a carrier daughter, and a 50% chance of having a child that does not inherit the mutated X-linked gene. ◆ Affected males have carrier daughters and unaffected sons because they pass their X chromosome to all of their daughters Y chromosome to all of their sons. ◆ A female occasionally exhibits signs of an X-linked trait similarly to a male. This occurs rarely owing to: - homozygosity for an X-linked trait. - the presence of a sex chromosome abnormality (45X0). - nonrandom X-inactivation. Examples of X-linked recessive diseases: Hemophilia A and B, Lesch Nyhan Syndrome, Hunter`s syndrome D.M.D., G6PD, and Color-blindness.

Answer 15

X-Linked Dominant Inheritance: + Female carriers typically manifest abnormal findings. + An affected man will have only affected daughters and unaffected sons. + Half of the offspring of an affected woman will be affected. + Some X-linked dominant conditions are lethal in a high percentageof males. Examples of X-linked dominant diseases: Incontinentia pigmenti, and vit.D resistant rickets.

Answer 16

Multifactorial and Polygenic Inheritance ◆ There is a similar rate of recurrence among all 1st-degree relatives (parents, siblings, offspring of the affected child). ◆ The risk of recurrence is related to the incidence of the disease. ◆ Some disorders have a sex predilection, as indicated by an unequal male : female incidence. Pyloric stenosis, for example, is more common in males, whereas congenital dislocation of the hips is more common in females. ◆ The risk of recurrence is increased when multiple family members are affected. ◆ The risk of recurrence may be greater when the disorder is more severe. Examples include pyloric stenosis, neural tube defects, congenital heart defects, diabetes, and cleft lip and cleft palate.

Answer 17

Down Syndrome - 1 in 733; the incidence at conception is more than twice that rate; the difference is accounted by early pregnancy losses. -The risk is highest in women who conceive at >35 yr of age. -All women should be offered screening for Down syndrome in their 2nd trimester by means of 4 maternal serum tests (free βhuman chorionic gonadotropin[β-hCG], unconjugated estriol, inhibin, and α-fetoprotein). This is known as the quad screen; it can detect up to 80% of Down syndrome pregnancies compared to 70% in the triple screen. In approximately 95% of the cases of Down syndrome there are 3 copies of chromosome 21.  95% of cases are due to non-disjunction (the supernumerary chromosome 21 is maternal in 97% of the cases). The incidence of this syndrome increased with maternal age from (1/750) of birth in those 30 years old to (1/365) in those >35 years, (1/100) in those 40 years old and (1/50) those >45 years.  1% due to mosiacism.  4% due to translocation involving chromosome 21. The majority of translocations in Down syndrome are fusions at the centromere between chromosomes 13, 14, 15, 21, and 22. Half of translocated cases were inherited from translocated carrier parent.. So chromosomal study must be done on every case of Down syndrome. If a translocation is identified, parental studies must be done. The recurrence risk for normal women <40 years old is 1%. If the mother is translocation carrier, the risk will be 10%. If the father is translocation carrier, the risk will be 3-5% . If the translocation is between (21, 21), the risk will be 100%. Clinical features CNS: Hypotonia, developmental delay, poor moro reflex, seizures. Craniofacial: Brachycephaly with flat occiput, flat face, upward slanted palpebral fissures, epicanthal folds, speckled irises (brushfield spots), nystagmus, strabismus, glaucoma, congenital or acquired cataract, three fontanels, delayed fontanel closure, frontal sinus and midfacial hypoplasia, mild microcephaly, short hard palate, small nose, flat nasal bridge, protruding tongue, open mouth. CVS(50%): Endocardial cushing defects(most characteristic), ventricular septal defect(most common), atrial septal defect, patent ductus arteriosus, pulmonary hypertension MSK: Joint hyperflexibility, short neck, redundant skin, short metacarpals and phalanges, short 5th digit with clinodactyly, single transverse palmar crease, wide gap between 1st and 2nd toes. Gastrointestinal: Duodenal atresia, annular pancreas, tracheoesophageal fistula, hirschsprung disease, imperforate anus, neonatal cholestasis. Cutaneous: Cutis marmorata. Up to 15% of children with Down syndrome have misalignment of cervical vertebra C1, which places them at risk for spinal cord injury with neck hyperextension or extreme flexion. Developmental delay is universal, social development is relatively spared, but children with Down syndrome have considerable difficulty using expressive language. Patient with Down syndrome had increased risk for hypothyrodism, diabetes mellitus, obesity, AML, ALL, problems with hearing and vision, Alzheimer disease, celiac disease, delayed tooth eruption, obstructive sleep apnea, and frequent infections . Most males are sterile; some females have been able to reproduce with 50% chance of having trisomy 21 pregnancies. Most adults with Down syndrome are able to perform activities of daily living. However, most adults with Down syndrome have difficulty with complex financial, legal, or medical decisions. The life expectancy is approximately 50-55 years.

Answer 18

Trisomy 18 (Edwards syndrome) Incidence: 1/6000 Head and Face: small and premature appearance, tight palpebral fissures, narrow nose and hypoplastic nasal alae, narrow bifrontal diameter, prominent occiput, micrognathia, cleft lip or palate, microcephaly. Chest: congenital heart disease (e.g., VSD, PDA, ASD), short sternum, small nipples. Extrimities: limited hip abduction, clinodactyly and overlapping fingers; index over 3rd, 5th over 4th; closed fist, rockerbottom feet, hypoplastic nails. General: severe developmental delays and prenatal and postnatal growth restriction, premature birth, polyhydramnios, inguinal or abdominal hernias, only 5% live >1 yr. Trisomy 13 (Patau syndrome) Incidence: 1/10000 Head and Face: scalp defects (e.g., cutis aplasia), microphthalmia, corneal abnormalities, cleft lip and palate in 60%-80% of cases, microcephaly, microphthalmia, sloping forehead, malformed ears, deafness. Chest: congenital heart disease (e.g., VSD, PDA, and ASD) in 80% of cases. Extrimities: overlapping of fingers and toes (clinodactyly), polydactyly, hypoplastic nails, hyperconvex nails. General: severe developmental delays and prenatal and postnatal growth restriction, renal abnormalities, early lethality in most cases, with a median survival of 7 days; 91% die by 1 year, only 5% live >6 mo.

Answer 19

Turner syndrome (45,X): The incidence is 1/5000 of live born females. Cytogenic aspects: Turner syndrome is a condition characterized by complete or partial monosomy of the X chromosome. 50% of patients have (45,X) and others are mosiasicim. In 75% of patients, the lost sex chromosome is of paternal origin (whether an X or a Y). Clinical features: The phenotype is female. # Newborns: small size for gestational age, webbing of the neck (redundant nuchal skin), protruding ears, and lymphedema of the hands and feet, although many newborns are phenotypically normal. # Older children and adults: short stature (cardinal finding in all girls) and exhibit variable dysmorphic features (increased carrying angle of elbow (cubitus valgus), scoliosis, broad chest with widely spaced nipples (shield chest), low posterior hairline, webbed neck). - Gonadal dysgenesis (infertility, primary amenorrhea, lack of secondary sex characters). - Congenital heart defects (40%) (bicuspid aortic valve, aortic stenosis, coarctation of aorta, mitral valve prolapse ), - Renal malformation in 60% (pelvic kidney, hoarseshoe kidney, double collecting system, complete absence of one kidney, and ureteropelvic junction obstruction), - Recurrent otitis media, sensorineural hearing loss. - Most patients tend to be of normal intelligence but learning disabilities is seen in 70%. Mental retardation is seen in 6% of affected children. - Females with 45,X/46,XY mosaicism have a 15-30% risk of developing gonadoblastoma. - There is increased incidence of acquired hypothyroidism, type 2 diabetes mellitus, inflammatory bowel disease, and celiac disease. Treatment: 1.Short stature: rhGH alone or in combination with anabolic steroid to increase heigh velocity. 2.Lack of secondary sex characters: Replacement with estrogen at 12-13 years. 3.If Y chromosome material is identified, laparoscopic gonadectomy is recommended.. 4.Infertility: Ovum donation and in vitro fertilization. 5.Psychosocial support. Noonan syndrome shares many clinical features with Turner syndrome, although it is an autosomal dominant disorder. Features common to Noonan syndrome include short stature, low posterior hairline, shield chest, congenital heart disease, and a short or webbed neck. Noonan syndrome has a different pattern of congenital heart disease typically involving right-sided lesions (left-sided lesion in turner syndrome).

Answer 20

Klinefelter syndrome The incidence is 1/575-1000 live born males. Cytogenic aspects: 80% of children with Klinefelter syndrome have a male karyotype with an extra chromosome X (47,XXY); the remaining 20% have multiple sex chromosome aneuploidies (48,XXXY; 49,XXXXY), or mosaicism (46,XY/47,XXY). The extra X chromosome is maternal in origin in 54% and paternal in origin in 46% of patients. Clinical features: Phenotypically is male with tall stature and have a specific tendency to have long legs (out of proportion to the arms). Patients develop secondary sex characters late and have sparser facial hair, 50% develop gynecomastia. Usually had azospermia, small testes and phallus and infertile (patients with 46,XY/47,XXY have a better prognosis for testicular function). Each additional X chromosome reduces the IQ by 10-15 points). Treatment: 1. Replacement therapy with long acting testosterone at (11-12) years of age. 2. Gynecomastia:  Medical treatment: may be treated with aromatase inhibitors (which will also increase endogenous testosterone levels).  Surgical treatment: indicate if: breast development is excessive causing significant psychologic distress or fails to regress in 18-24 mo after therapy. 3. Infertility:testicular sperm extraction (TSE) followed by intracytoplasmic sperm injection. 4. Counseling and psychiatric services should be provided as needed.

Answer 21

Diphtheria (Corynebacterium diphtheriae) ETIOLOGY: Corynebacteria are aerobic, nonencapsulated, non–spore-forming, mostly nonmotile, Grampositive bacilli . Spread is primarily by airborne respiratory droplets, direct contact with respiratory secretions of symptomatic individuals, or exudate from infected skin lesions. Skin infection and skin carriage are silent reservoirs of C. diphtheriae, and organisms can remain viable in dust or on fomites for up to 6m. PATHOGENESIS: local inflammatory reaction, causes local tissue necrosis. a dense necrotic coagulum of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes forms a gray-brown, leather-like adherent pseudomembrane (Diphthera is Greek for leather). Removal is difficult and reveals a bleeding edematous submucosa. Paralysis of the palate and hypopharynx is an early local effect of diphtheritic toxin. Toxin absorption can lead to systemic manifestations: kidney tubule necrosis, thrombocytopenia, cardiomyopathy, and/or demyelination of nerves( Because the latter 2 complications can occur 2-10 wk after mucocutaneous infection, the pathophysiology in some cases is suspected to be immunologically mediated) CLINICAL MANIFESTATIONS: ## Respiratory Tract Diphtheria The primary focus of infection was the tonsils or pharynx (94%), with the nose and larynx the next 2 most common sites. After an average incubation period of 2-4 days, local signs and symptoms of inflammation develop. Infection of the anterior nares causes serosanguineous, purulent, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. Mild pharyngeal injection is followed by unilateral or bilateral tonsillar membrane formation, (which can extend to involve the uvula, soft palate, posterior oropharynx, hypopharynx, or glottic areas). Underlying soft-tissue edema and enlarged lymph nodes can cause a bull-neck appearance. Hoarseness, stridor, dyspnea, and croupy cough are clues … and the fatality due to airway compromise or toxin-mediated complications. Note \\ The characteristic adherent membrane, and relative lack of fever help differentiate diphtheria from exudative pharyngitis caused by Streptococcus pyogenes or Epstein-Barr virus. Patients with laryngeal diphtheria are at significant risk for suffocation because of local soft-tissue edema and airway obstruction by the diphtheritic membrane. Establishment of an artificial airway and resection of the pseudomembrane can be lifesaving. ## Cutaneous Diphtheria: Classic cutaneous diphtheria is an indolent, nonprogressive infection characterized by a superficial, ecthyma-like, nonhealing ulcer with a gray-brown membrane. Extremities are more often affected than the trunk or head . Pain, tenderness, erythema, and exudate are typical. DIAGNOSIS: ## Specimens for culture should be obtained from the nose and throat and any other mucocutaneous lesion. A portion of membrane should be removed and submitted for culture along with underlying exudate. ## Toxigenicity and antimicrobial susceptibility tests should be performed for C. diphtheriae isolates. COMPLICATIONS: ## Respiratory tract obstruction by pseudomembranes may require bronchoscopy or intubation and mechanical ventilation. ## Toxic cardiomyopathy occurs in 10-25% of patients with respiratory diphtheria and is responsible for 5060% of deaths. Tachycardia disproportionate to fever is common and may be evidence of cardiac toxicity or autonomic nervous system dysfunction. ## Toxic Neuropathy: Acutely or 2-3 wk after onset of oropharyngeal inflammation, it is common for local paralysis of the soft palate to occur. Weakness of the posterior pharyngeal, laryngeal, and facial nerves may follow, causing a nasal quality in the voice, difficulty in swallowing, and risk for aspiration. Cranial neuropathies characteristically occur in the 5th wk, leading to oculomotor and ciliary paralysis, which can cause strabismus, blurred vision, or difficulty with accommodation. Symmetric polyneuropathy has its onset 10 days to 3 mo after oropharyngeal infection and causes principally motor deficits with diminished deep tendon reflexes. Distal muscle weakness in the extremities with proximal progression is more commonly described than proximal muscle weakness with distal progression. Recovery from the myocarditis and neuritis is often slow but usually complete. TREATMENT: Specific antitoxin is the mainstay of therapy Equine diphtheria antitoxin is available. Antitoxin is administered as a single empirical dose of 20,000-100,000 units # Antitoxin is probably of no value for local manifestations of cutaneous diphtheria. # Antitoxin is not recommended for asymptomatic carriers. The role of antimicrobial therapy is to : 1-halt toxin production, 2-treat localized infection, 3- prevent transmission of the organism to contacts. Appropriate therapy is ## Erythromycin (40-50 mg/kg/day divided every 6 hr by mouth [PO] Or intravenously [IV]; maximum 2 g/day), ## aqueous crystalline penicillin G (100,000-150,000 units/kg/day divided every 6 hr IV for 14 days. Note\Elimination of the organism should be documented by negative results of at least 2 successive cultures of specimens from the nose and throat (or skin) obtained 24 hr apart after completion of therapy.

Answer 22

TETANUS It is an illness characterized by an acute onset of hypertonia, painful muscular contractions (usually of the muscles of the jaw and neck), and generalized muscle spasms without other apparent medical causes. # Tetanus is an infection caused by bacteria called Clostridium tetani (anerobic bacteria ) fatal bacterial infection that affects the nerves. # they produce a toxin (Tetanospasmin) PATHOGENESIS # Tetanus toxin, called tetanospasmin. It is transported from an infected locus by retrograde neuronal flow or blood # Blocks the inhibitory neurotransmitters resulting in a sustained muscle contraction # The incubation period may range from 3 - 21 days . Signs and symptoms ; • Tetanic seizures (painful, powerful bursts of muscle contractions) • stiffness of jaw (also called lockjaw) • intractable spasms of facial and buccal muscles (risus sardonicus) • stiffness of abdominal and back muscles • opisthotonus is defined as a dramatic abnormal posture due to spastic contraction of the extensor muscles of the neck, trunk, and lower extremitie • if the muscle spasms affect the larynx or chest wall, they may cause asphyxiation • hypertention, tachycardia, and diaphoresis • fever and sweating • Headache. • Because tetanus toxin does not affect sensory nerves or cortical function, the patient unfortunately remains conscious, in extreme pain, and in fearful anticipation of the next tetanic seizure. DIGNOSIS: The diagnosis may be established clinically. The typical setting is an unimmunized patient (and/or mother) who was injured or born within the preceding 2 wk, who presents with trismus, other rigid muscles, and clear sensorium. Results of routine laboratory studies are usually normal. A peripheral leukocytosis may result from a secondary bacterial infection of the wound or may be stress induced from sustained tetanic spasms. The CSF is normal. EEG and EMG do not show a characteristic pattern. C. tetani is not always visible on Gram stain of wound material and is isolated in only approximately 30% of cases. TREATMENT # Management requires eradication of C.tetani and the wound environment conductive to its anaerobic multiplication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation, provision of meticulous supportive care( protection from unnecessary sounds, sights, and touch in a quiet, dark and scheduled setting), and prevention of recurrences. # Surgical wound excision and debridement to remove the foreign body or devitalized tissue after administration of human tetanus immunoglobulin (TIG)(as soon as possible) and antibiotics. # Penicillin G ( 100,000 units/kg/day divided every 4-6 hr IV for 10-14 days) remains of choice because of its effective clostridiocidal action and its diffusibility. # Metronidazole (500 mg every 8 hr IV for adults) also effective. # For penicillin-allergic patients, erythromycin and tetracycline are alternatives. # Muscle relaxant like diazepam ( relaxation and seizure control) # For autonomic instability is regulated with α- or β- or both blocking agents. # neuromuscular blocking agents and mechanical ventilation. COMPLICATIONS: = Aspiration of secretions and pneumonia. = Complications of endotracheal intubation and mechanical ventilation including pneumothorax and mediastinal emphysema. = The seizures may result in laceration of the mouth or tongue, intramuscular hematoma, rhabdomyolysis with myoglobinuria and renal failure, or in long bone or spinal fractures. = Venous thrombosis, pulmonary embolism, gastric ulceration. = Cardiac arrhythmias, unstable blood pressure, labile temperature regulation. PROGNOSIS: Favourable prognosis : + long incubation period + absence of fever + localized disease Unfavourable prognosis: + very young and very old + trismus onset >7 days after injury and generalized tetanic spasms >3 days .. after onset of trismus + cephalic tetanus PREVENTION: -Tetanus is an entirely preventable disease. -A serum antibody titer of ≤0.01 units/mL is considered protective. -Active immunization should begin in early infancy with combined diphtheria toxoid-tetanus-toxoid acellular pertussis (DTaP) vaccine at 2, 4, 6 and 15-18 mo of age, with boosters at 4-6 yr (DTaP) and 11-12 yr (Tdap) of age and at 10 yr intervals thereafter throughout adult life with tetanus and reduced diphtheria toxoid (Td). -Immunization of women with tetanus toxoid prevents neonatal tetanus, and pregnant women should receive reduced diphtheria and pertussis toxoids (Tdap) preferably at 27-36 wk gestation. WOUND MANAGEMENT: *The wound should undergo immediate, thorough surgical cleansing and debridement to remove foreign bodies and any necrotic tissue in which anaerobic conditions might develop. *Tetanus prevention measures after trauma consist of inducing active immunity to tetanus toxin and of passively providing antitoxic antibody. *Tetanus toxoid should be given after a dog or other animal bite. *All nonminor wounds require human TIG except those in a fully immunized patient. In any other circumstances (e.g., patients with an unknown or incomplete immunization history; crush, puncture, or projectile wounds; wounds contaminated with saliva, soil, or feces; avulsion injuries; compound fractures; or frostbite), TIG 250 units should be given intramuscularly, with 500 units for highly tetanus-prone wounds (i.e., unable to be debrided, with substantial bacterial contamination, or longer than 24 hr since injury). *A tetanus toxoid booster is administered to all persons with any wound if the tetanus immunization status is unknown or incomplete. *A booster is administered to injured persons who have completed the primary immunization series if:(1) the wound is clean and minor but 10 or more years have passed since the last boster or (2) the wound is more serious and 5 or more years have passed since the last booster.

Answer 23

Normal growth is one of the fundamental characteristics of childhood and adolescence. Deviation from a normal pattern of growth can be the first manifestation of a wide variety of disease processes, and early recognition of poor growth allows early intervention optimizing the possibility of achieving: • Good health, and • Normal adult height NORMAL GROWTH Phases of human growth can be divided into: Prenatal: Birth size predominantly relating to maternal factors rather than fetal factors. It influenced by maternal nutrition, maternal size, maternal health, placental factors, intrauterine infection , and endocrine factors (IGF2). It has the fastest growth rate. Post natal growth: It is more dependent on the infant’s genetic background, and it influenced predominantly by: • Infancy : nutrition • Childhood : thyroxin, GH • Puberty : GH , sex hormones

Answer 24

GROWTH ASSESSMENT It is achieved by assessment of the followings: • Supine lenghth Lt (≤2 yr) using length board with full extension and in a Frankfurt plane (the line between outer canthus and external auditory meatus is perpendicular to the long axis of the trunk), or Standing height Ht (>2 yr) using wall-mounted stadiometer with the back of the head, thoracic spine, buttocks, and heels, which are placed together, touching the vertical plane of the stadiometer and in Frankfurt plane. • Upper segment-to-lower segment ratio (ULR): assess sitting Ht (upper) and then subtract it from total Ht (lower). Normal U/L ratio is 1.7 at birth, 1.3 at 3 yr, and 1 at 10 yr. • Arm span: assess the distance between the 2 middle fingers while outstretching the arms parallel to ground. Normal arm span is about Ht ± 5 cm. • Weight using beam balance or electronic scale • OFC, BMI • Pubertal stage using Tanner staging. • Midparental height (MPH): helps to determine if the child is growing well for the family. It calculated as follow: for male = (mother ht cm + father ht cm +13)/2 for female = (mother ht cm +father ht cm -13)/2 The range of normal height for the child = MPH ± 10 cm • Growth velocity GV determines the change in height over time. It is calculated as the difference in height on two different occasions over 6-12 moths, provided that Hts had been measured at same time of the day (as normally there is diurnal variation in the Ht due to fatigue of the spine musculature throughout the day).it depends on gender, age and pubertal status. Changes in growth velocity allow earlier identification of growth problems as changes in actual height are only evident after growth velocity has been reduced for a period of time. There is specific chart for it, but roughly: Infancy : 22cm/y Childhood : 5-7cm/y Puberty : 10-12 cm/y Growth charts: accurate age (date of birth) has a crucial role, and growth parameters should be plotted on a growth charts of the same sex. Classical charts have the following percentile; 3 rd or 5th , 10th , 25th , 50th , 75th , 90th , 95 th 0r 97th . As we don't have Iraqi growth charts so we depend on CDC or WHO growth charts. Disease-related growth charts have been developed for Turner syndrome, achondroplasia, and Down syndrome.

Answer 25

Short stature SS is defined as Ht greater than 2 standard deviations (SDs) below the mean Ht for sex and chronological age (~ <3 rd %). Dwarfism refers to severe forms of SS with Ht below 3 SD from the mean. If the Ht is within the normal percentile but GV is below 3rd percentile, it is also considered as abnormal and need same approach as short stature. CAUSES • Nonpathologic causes (normal GV) -Genetic (familial) SS. -Constitutional SS. • Pathologic causes (decrease GV) :Primary growth disorders Chromosomal as Turner syndrome, Prader Willi syndrome, SHOX deficiency, etc…. o Skeletal dysplasia as achondroplasia. o IUGR. -Secondary growth disorders -Endocrinopathies :GH deficiency or insensitivity ,Hypothyroidism ,Cushing ,Pseudo or pseudopseudo-hypoparathyroidism o Malnutrition. o Rickets. o Chronic disease. o Psychosocial dwarfism. • Idiopathic SS: ss that can’t be explained by the aforementioned causes ( normal or decrease GV). CLASSIFICATION -may be classified according to ULR into: 1. Disproportionate SS (high ULR): skeletal dysplasia, rickets, hypothyroidism, Turner syndrome. 2. Proportionate SS (normal ULR): all other causes. Genetic (familial) ss: -Normal GV -No systemic illness, normal physical examination. -Ht within MPH -Bone age= chronological age -Normal puberty -Short adult height (reflective of the parents) Constitutional ss: -Normal birth wt and Ht, decelerated growth 12-30 months of age, by 3 yr of age begin normal GV. -No systemic illness, normal physical examination. -Ht < MPH -Bone age< chronological age -Delayed puberty -Normal adult Ht (reflective of the parents) -Family history of similar growth pattern

Answer 26

GH deficiency GHD: It may be due to hypothalamic or pituitary dysfunction, congenital or acquired due to tumor, trauma, infection, irradiation. -Decrease GV. -Ht < MPH -Bone age< chronological age. -short adult Ht (not reflective of the parents) MANAGEMENT History: a detailed history is the key to eliciting the etiology of short stature and should include the following elements: • Prenatal history (maternal infection, drugs, smoking,….). • Birth weight and length in relation to gestational age. • Family history: FH of ss, age of onset of puberty in parents and immediate relatives. • Pubertal development. • Nutritional history. • Evidence of systemic disease: gastrointestinal (GI), cardiac, pulmonary, renal, etc….. • Drug administration: glucocorticoids. • Neurologic symptoms: especially headache, visual disturbance, recent history of enuresis (CNS tumor). • History of CNS infection, head trauma, irradiation. • Psychosocial milieu. Examination: a comprehensive physical examination should be conducted with special emphasis on the following: • Growth assessment as mentioned above. • Dysmorphic features. • Examination of the thyroid gland. • Complete neurological exam including fundoscopy and visual fields. Three rules of pediatric endocrinology: 1. Tall and overweight = Simple obesity 2. Short and overweight = Endocrine disorders 3. Short and underweight = Chronic illness or malnutrition Investigations: 1. BA (X ray of hand & wrist) assessment: it estimated from the appearance of the epiphyses of the left wrist and hand, reflecting physical maturity and may be considered a sort of “biological age. Itself is not diagnostic but can be used to aid in arriving at a diagnosis as follow: Delayed BA: constitutional ss, endocrine causes, malnutrition, chronic diseases. Appropriate BA: familial ss, syndromes, bone dysplasia. 2. TFT (hypothyroidism), karyotype in female (Turner syndrome), CBC and ESR (infection, inflammation, anemia), RFT and urine exam (renal disease), Antitissue transglutaminase Ig A and total Ig A (celiac disease), S. Ca, phosphate, ALP. If the results of these investigations are normal, proceed to 3. 3. Fasting IGF-1 and GH assay. As the secretion of GH is pulsatile, GH assay should be basal and after stimulation. Two of the following GH stimulation tests are required for diagnosis of GHD (clonidine, arginine, insulin, glucagon, levodopa, propranolol). 4. Pituitary MRI in GHD patient. Treatment: • Counseling of parents for physiological causes (constitutional and familial ss) • Treatment of underlying cause (hypothyroidism, Cushing, celiac, …….) • GH therapy: FDA approved indications are: • GHD. • Turner syndrome. • Chronic renal failure before transplantation • SGA and lack of catch-up growth by 3-4 yr. • Prader Willi syndrome. • Idiopathic ss. • Noonan syndrome. • SHOX deficiency. Criteria for stopping GH therapy are: 1. A decision by the patient that she or he is tall enough, or 2. GV < 1 inch / yr, or 3. BA > 14 years in girls and >16 years in boys Side effects GH therapy: 1. DMT2 2. Slipped femoral epiphysis 3. worsening of scoliosis 4. Psuedotumor cerebi 5. Gynecomastia 6. No increase in incidence of leukemia nor recurrence of craniopharyngioma and other brain tumor, but increase the risk of 2 nd neoplasm in cancer survivors.

Answer 27

HYPOTHYROIDISM Definition: Deficiency of thyroid hormone production that result from either defect in thyroid gland itself (primary hypothyroidism, most common) or reduced TSH stimulation (central hypothyroidism). Classification: • • Congenital hypothyroidism a. Primary hypothyroidism ▪ Defect in fetal thyroid development (dysgenesis) 80%. ▪ Defect in thyroid hormone synthesis (dyshormonogenesis) 15%. ▪ TSH unresponsiveness. ▪ Maternal iodine deficiency. ▪ Maternal antibodies: thyrotropin receptor–blocking antibody. ▪ Maternal medication (iodide, amiodarone, antithyroid medication, radioiodine). b. Central hypothyroidism ▪ Isolated TSH or TRH deficiency. ▪ Multiple congenital pituitary hormones deficiency. Acquired hypothyroidism a. Primary hypothyroidism ▪ Autoimmune (most common). ▪ Drug induced (excessive iodide, amiodarone, medication, anticonvulsants). ▪ Postablative (irradiation, thyroidectomy). antithyroid ▪ Systemic infiltrative disease. b. Central hypothyroidism (head trauma, tumor, radiation). Clinical features: Congenital hypothyroidism: Most infants with congenital hypothyroidism are asymptomatic at birth, attributed to partial transplacental passage of maternal T4, which provides fetal levels that are approximately 33% of normal at birth. Despite this maternal contribution, hypothyroid infants still have a low serum T4 and elevated TSH level on screening programs (protect the infant but not interfere with screening). While breast milk contains significant amounts of thyroid hormones, it neither protect the hypothyroid infant nor affect neonatal thyroid screening tests. At birth; birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain. The anterior and posterior fontanels are open widely. During the 1st mo of life; prolongation of physiologic jaundice (delayed maturation of glucuronide conjugation), feeding difficulties (sluggishness, lack of interest, somnolence, and choking spells during nursing), and respiratory difficulties(apneic episodes, noisy respirations, and nasal obstruction) partly caused by the large tongue. During infancy; respiratory distress, cry little, sleep much, have poor appetites, and are generally sluggish. There may be constipation, large abdomen, umbilical hernia, subnormal temperature (often <35°C), cold and mottled skin (particularly that of the extremities), edema of the genitals and extremities, slow pulse, heart murmurs, cardiomegaly, asymptomatic pericardial effusion. Approximately 10% of infants with congenital hypothyroidism have associated congenital anomalies, including: cardiac anomalies (most common), nervous system and eye anomalies, hearing loss, cleft palate, genitourinary anomalies. Because symptoms appear gradually, the clinical diagnosis is often delayed. If congenital hypothyroidism goes undetected and untreated, these manifestations progress. So there will be retardation of physical and mental development, and by 3-6 mo of age the clinical picture is fully developed. Fully developed clinical picture; growth will be stunted, the extremities are short, the head size is normal or even increased, the anterior fontanel is large and the posterior fontanel may remain open, the eyes appear far apart, the bridge of the broad nose is depressed, the palpebral fissures are narrow and the eyelids are swollen, the mouth is kept open, and the thick, broad tongue protrudes, dentition will be delayed, the neck is short and thick, the hands are broad and the fingers are short, the skin is dry and scaly, and there is little perspiration, myxedema (particularly in the skin of the eyelids, the back of the hands, and the external genitals), the skin shows general pallor with a sallow complexion, carotenemia (yellow discoloration of the skin, but the sclerae remain white), the scalp is thickened, and the hair is coarse, brittle, and scanty, the hairline reaches far down on the forehead, which usually appears wrinkled, especially when the infant cries, developmental delayed (late in learning to sit and stand), the voice is hoarse, and they do not learn to talk. The degree of physical and intellectual delay increases with age. Sexual maturation may also be delayed or might not take place at all. The muscles are usually hypotonic, but in rare instances generalized muscular pseudohypertrophy occurs (Kocher-Debré-Sémélaigne syndrome): it affects patients who have hypothyroidism of longer duration and severity. Boys are more prone to development of this syndrome who presented with athletic appearance because of pseudohypertrophy, particularly in the calf muscles. Its pathogenesis is unknown, and it returns to normal with treatment.

Answer 28

Acquired hypothyroidism: deceleration of growth (usually the first clinical manifestation, but often goes unrecognized), goiter (associated with Hashimoto thyroiditis may be a presenting feature), weight gain (mostly fluid retention (myxedema) not true obesity), myxedematous changes of the skin, constipation, cold intolerance, decreased energy, and an increased need for sleep. Surprisingly, schoolwork and grades usually do not suffer, even in severely hypothyroid children. Additional features include bradycardia, muscle weakness or cramps, nerve entrapment, and ataxia. About puberty: • Older adolescent girls manifest menometrorrhagia. • Adolescents typically have delayed puberty. • Younger children might present with galactorrhea (increased TRH stimulating prolactin secretion) or pseudoprecocious puberty characterized by breast development and vaginal bleeding in girls and macroorchidism in boys (high TSH concentrations binding to the FSH receptor with subsequent stimulation). Some children have headaches and vision problems; they usually have hyperplastic enlargement of the pituitary gland due to long-standing primary hypothyroidism. It may be mistaken for a pituitary tumor. IX :- 1. TFT FT4: low TSH: high in primary hypothyroidism, normal or low in central one. 2. Thyroid antibodies: antithyroglobulin and antiperoxidase antibodies can pinpoint autoimmune thyroiditis as the cause. 3. Thyroid sonography: generally, not indicated unless there is a suspicion of a thyroid nodule on neck palpation 4. X ray for bone age: osseous maturation is delayed, which is an indication of the duration of the hypothyroidism. 5. Abnormal laboratory findings, include hyponatremia, macrocytic anemia (refractory to treatment with hematinics), hypercholesterolemia, and elevated creatine phosphokinase. Treatment: Oral levothyroxin once daily at fixed time (standard recommendation is on an empty stomach, 0.5-1 hr before breakfast). BASIC (bile acid binding resine, aluminum containing antiacid, soy, iron, calcium and caffeine) interfere with thyroxin absorption. levothyroxin doses per weight decrease with increasing age (for example, neonates 10-15 Ug/kg/day, while those ≥ 10 yr 2-4 Ug/kg/day). Treatment should be monitored by measuring serum free T4 and TSH every 4-6 mo as well as 6 wk after any change in dosage. The target is normalization of both free T4 and TSH level.

Answer 29

Congenital hypothyroidism: The early approach to newborn screening began with measure of levels of T4, followed by measurement of TSH when T4 is low. Over time, many neonatal screening programs elsewhere in the world have switched to an initial TSH measurement. Regardless of the approach used for screening, some infants escape detection because of technical or human errors; clinicians must maintain their vigilance for clinical manifestations of hypothyroidism. In identical twins; transfusion of euthyroid blood from the unaffected twin may normalized the serum levels of T4 and TSH in the affected twin at the initial screening and the diagnosis was not made until the infants were 4-5 mo of age. Many newborn screening programs perform a routine second test in same-sex twins. IX:- 1. TFT FT4: low T3 may be normal and are not helpful in the diagnosis. TSH: high in primary hypothyroidism, normal or low in central one. 2. Serum levels of thyroglobulin are usually low in thyroid agenesis or defects of thyroglobulin synthesis or secretion. 3. Radiography: The distal femoral and proximal tibial epiphyses, normally present at birth, are often absent ( mean retardation of osseous development which occurs in approximately 60% of hypothyroid infants). Cardiac enlargement or pericardial effusion may be present. 4. Scintigraphy pinpoint the underlying cause in infants with congenital hypothyroidism, also ultrasonographic examination of the thyroid is helpful. 5. ECG: may show low-voltage P and T waves with diminished amplitude of QRS. 6. Echocardiography can confirm a pericardial effusion. 7. EEG: often shows low voltage. 8. The serum cholesterol level is usually elevated in children older than 2 yr of age. In congenital hypothyroidism, rapid normalization of thyroid function (ideally within 2 wk) is important in achieving optimal neurodevelopmental outcome.

Answer 30

Hemophilia A (factor VIII deficiency ) and hemophilia B (factor IX deficiency) are the most common and serious congenital coagulation factor deficiencies . The clinical findings in hemophilia A and hemophilia B are identical. Hemophilia C is the bleeding disorder associated with reduced levels of factor XI . Factor VIII or Factor IX Deficiency (Hemophilia A or B) Deficiencies of factors VIII and IX are the most common sever inherited bleeding disorders. Pathophysiology: Factor VIII and IX with phospholipid and calcium , they form the tenase or factor X activating complex. Factor X being activated by either (complex of factor VIII and IX) or (the complex of tissue factor and factor VII) . . In hemophilia A and B ,due to inadequate thrombin generation leads to failure to form a tightly cross- linked fibrin clot to support the platelet plug . When untreated bleeding occurs in closed space, such as joint cessation of bleeding may be the result of tamponade. With open wounds ,in which tamponade cannot occur, bleeding may result in significant blood loss. Clinical Manifestations: Neither factor VIII nor factor IX crosses the placenta , bleeding symptoms may be present from birth or may occur in the fetus. Only 2% of neonates with hemophilia sustain intracranial hemorrhages, and 30% of male infants with hemophilia bleed with circumcision. In the absence of a positive family history (30% of hemophilia A occurs by spontaneous mutation), hemophilia may go undiagnosed in the newborn. Obvious symptoms, such as easy bruising, intramuscular hematomas, and hem arthroses , begin when the child starts to cruise. Bleeding from minor traumatic lacerations of the mouth (torn frenulum) may persist for hours or days and may cause the parents to seek medical evaluation. Although bleeding may occur in any area of the body, the hallmark of hemophilic bleeding is hem arthrosis. Bleeding into the joints may be induced by minor trauma; many hem arthroses are spontaneous. The earliest joint hemorrhages appear most often in the ankle. In the older child and adolescent, hem arthroses of the knees and elbows are also common. The child's early joint hemorrhages are recognized only after major swelling and fluid accumulation in the joint space, but older children complain of a warm, tingling sensation in the joint as the first sign of an early joint hemorrhage. Repeated bleeding episodes into the same joint in a patient with severe hemophilia may result in a “target” joint. Recurrent bleeding may then become spontaneous because of the underlying pathologic changes in the joint Although most muscular hemorrhages are clinically evident because of localized pain or swelling, bleeding into the iliopsoas muscle requires specific attention . A patient may lose large volumes of blood into the iliopsoas muscle, leading to hypovolemic shock, with only a vague area of referred pain in the groin. The hip is held in a flexed, internally rotated position due to irritation of the iliopsoas. The diagnosis is made clinically from the inability to extend the hip but must be confirmed with ultrasonography or CT scan. Life- threatening bleeding in the patient with hemophilia is caused by bleeding into vital structures (central nervous system, upper airway) or by obtaining (external trauma, gastrointestinal or iliopsoas hemorrhage). Argent treatment with clotting factor concentrate for these lifethreatening hemorrhages is essential. If head trauma is of sufficient concern to suggest radiologic evaluation, factor replacement should precede radiologic evaluation.

Answer 31

Laboratory Findings and Diagnosis : A reduced level of factor VIII or factor IX will result in a laboratory finding of a prolonged PTT. In severe hemophilia, the PTT value is usually 2-3 times the upper limit of normal. Other screening tests of the hemostatic mechanism (platelet count, bleeding time, PT, thrombin time) are normal. Unless the patient has an inhibitor to factor VIII or IX, the mixing of normal plasma with patient plasma results in correction of PTT value. The specific assay for factors VIII and IX will confirm the diagnosis of hemophilia. If correction does not occur on mixing, an inhibitor may be present. In 25–35% of patients with hemophilia who receive infusions of factor VIII or factor IX, a factor-specific antibody may develop (inhibitors). In such patients, the quantitative Bethesda assay for inhibitors should be performed to measure the antibody titer. Differential Diagnosis : Severe thrombocytopenia; severe platelet function disorders, such as Bernard-Soulier syndrome and Glanzmann thrombasthenia; type 3 (severe) von Willebrand disease; and vitamin K deficiency. Genetics and Classification : Hemophilia occurs in approximately 1 : 5,000 males, with 85% having factor VIII deficiency and 10–15% having factor IX deficiency. Hemophilia shows no apparent racial predilection, appearing in all ethnic groups. Severe hemophilia is characterized as having <1% activity of the specific clotting factor, and bleeding is often spontaneous. Moderate hemophilia have factor levels of 1–5% and usually require mild trauma to induce bleeding. Mild hemophilia have levels >5%, may go many years before the condition is diagnosed, and frequently require significant trauma to cause bleeding. Hemostatic level for factor VIII is >30–40%, and for factor IX, it is >25-30%. Lower limit of levels for factors VIII and IX in normal individuals is approximately 50%. The genes for factors VIII and IX are carried near the terminus of the long arm of the X chromosome and are therefore X-linked traits. Approximately 45–50% of patients with severe hemophilia A have the same mutation, which can be detected in the blood of patients or carriers and in the amniotic fluid by molecular techniques.

Answer 32

Treatment : Patients with haemophilia are best managed through comprehensive hemophilia care centers. Early, appropriate therapy is the hallmark of excellent hemophilia care . When mild to moderate bleeding occurs, values of factor VIII or factor IX must be raised to hemostatic levels, in the 35–50% range. For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity. Calculation of the dose of recombinant factor VIII (FVIII) as fallows : Dose of rF VIII(IU) = % Desired (rise in F VIII)× Body weight (Kg) × 0.5 Prophylaxis is the standard of care for most children with severe hemophilia, to prevent spontaneous bleeding and early joint deformities. If target joints develop, “secondary” prophylaxis is often initiated. With mild factor VIII hemophilia, the patient's endogenously produced factor VIII can be released by the administration of desmopressin acetate . In patients with moderate or severe factor VIII deficiency, the stored levels of factor VIII in the body are inadequate, and desmopressin treatment is ineffective . A concentrated intranasal form of desmopressin acetate, , can also be used to treat patients with mild hemophilia A. The dose is 150 µg (1 spray) for children weighing <50 kg and 300 µg (2 sprays) for children and young adults weighing >50 kg. Desmopressin is not effective in the treatment of factor IX–deficient hemophilia. Preliminary trials of factor IX gene therapy are underway with some encouraging initial results. Mucosal bleeding may require adjunct use of an antifibrinolytic such as aminocaproic acid or tranexemic acid. Once-weekly prophylactic subcutaneous injections of emicizumab (humanized monoclonal antibody) may be able to reduce the rate of bleeding in patients with or without factor VIII inhibitors. Supportive Care : Although it is easy to tell parents that their child should avoid trauma, this advice is not practical in active children and adolescents. Effective measures include anticipatory guidance, including the use of car seats, seatbelts, and bike helmets and the avoidance of highrisk behaviors. Older boys should be counseled to avoid violent contact sports . Boys with severe hemophilia often sustain hemorrhages in the absence of known trauma. Early psychosocial intervention helps the family achieve a balance between overprotection and permissiveness. Patients with hemophilia should avoid aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) that affect platelet function. The child with a bleeding disorder should receive the appropriate vaccinations against hepatitis B, even though recombinant products may avoid exposure to transfusion-transmitted diseases. Patients exposed to plasma-derived products should be screened periodically for hepatitis B and C, HIV, and abnormalities in liver function.

Answer 33

Chronic Complications : 1-Chronic arthropathy . 2-The development of an inhibitor to either factor VIII or factor IX 3-The risk of transfusion-transmitted infectious diseases. Inhibitor Formation : Failure of a bleeding episode to respond to appropriate replacement therapy is usually the first sign of an inhibitor.Inhibitors develop in approximately 25–35% of patients with hemophilia A but only 2–3% of patients with hemophilia B . Rituximab, corticosteroids, and other immunosuppressive have all been used as alternate therapy for patients with high inhibitor titers in whom immune tolerance programs have failed. Emicizumab may be another approach for patients with inhibitors

Answer 34

Factor XI deficiency : ( Hemophilia C ) Autosomal deficiency associated with mild to moderate bleeding symptoms. The bleeding tendency is not as severe as in factor VIII or Treatment : Local pressure , antifibrenolytic drugs and Fresh Frozen Plasma (FFP). factor IX deficiency. Factor V Deficiency (parahemophilia ) : It is an autosomal recessive, mild to moderate bleeding disorder . Hemarthroses occur rarely ; mucocutaneous bleeding and hematomas are the most common symptoms. Severe menorrhagia is a frequent symptom in women. Laboratory evaluation shows prolonged PTT and PT. Factor V assays show a reduction in factor V levels. FFP is the only currently available therapeutic product that contains factor V. Factor VII deficiency: It is a rare autosomal bleeding disorder that is usually detected only in the homozygous state. Severity of bleeding varies from mild to severe with hemarthroses, spontaneous intracranial hemorrhage, and mucocutaneous bleeding, especially epistaxis and menorrhagia. Patients with this deficiency have greatly prolonged PT but normal PTT. Factor VII assays show a marked reduction in factor VII. Because the plasma half-life of factor VII is 2-4 hr, therapy with FFP is difficult and is often complicated by fluid overload. A commercial concentrate of recombinant factor VIIa is effective in treating patients with factor VII deficiency. Factor XIII : Because factor XIII is responsible for the cross linking of fibrin to stabilize the fibrin clot, symptoms of delayed hemorrhage are secondary to instability of the clot. Typically, patients have trauma 1 day and then have a bruise or hematoma the next day. Clinical symptoms include mild bruising, delayed separation of the umbilical stump beyond 4 wk in neonates, poor wound healing, and recurrent spontaneous abortions in women and rarely hemarthroses and intracranial hemorrhage have been described. Results of the usual screening tests for hemostasis are normal . Increased solubility of the clot because of the failure of cross linking. The normal clot remains insoluble in the presence of 5M urea, but in a patient with factor XIII deficiency, the clot dissolves. More specific assays for factor XIII are immunologic. The half-life of factor XIII is 5-7 days, and the hemostatic level is 2–3% activity. There is a heat-treated, lyophilized concentrate of coagulation factor XIII available to treat bleeding episodes or for prophylaxis.

Answer 35

Von Willebrand Disease : Objective : Types , Clinical presentations , Diagnosis , Treatment . It is the most common inherited bleeding disorder, Prevalence cited at 1 : 100 to 1 : 10,000 depending on the criteria used for diagnosis. Patients with VWD typically present with mucosal bleeding. A family history of either VWD or bleeding symptoms and confirmatory laboratory testing are also required for the diagnosis of VWD. Epistaxis, easy bruising, and menorrhagia in women are common complaints. Symptoms are variable and do not necessarily correlate well with VWF levels. Surgical bleeding, especially with dental extractions or adenotonsillectomy, is another common presentation. Severe type 3 VWD may present as mild hemophilia with joint bleeds and intracranial hemorrhage. Most patients will have a family history of bleeding. Women are more likely to be diagnosed with VWD because of the potential for symptoms with menorrhagia, but men and women are equally likely to have VWD. However, diagnosis based on symptoms may be difficult, since minor bruising and epistaxis are not uncommon in childhood . Classification : VWD may be caused by quantitative or qualitative defects in VWF. Mild to moderate quantitative defects are classified as type 1 VWD, The qualitative defects are grouped together as type 2 VWD. Severe quantitative defects, in which there is no detectable VWF protein, are classified as type 3 VWD. Type 1 VWD is the most common type, accounting for 60–80% of all VWD patients. Typical symptoms include mucosal bleeding, such as epistaxis and menorrhagia, as well as easy bruising and potentially surgical bleeding. Patients with type 1 VWD may have low VWF as a result of increased clearance of their VWF, or type 1C VWD . Diagnosis of this subtype is important because treatment of these patients with desmopressin is likely to be ineffective, necessitating administration of VWF-containing products . Type 3 VWD is the most severe form and presents with symptoms similar to those seen in mild hemophilia. In type 3 VWD the VWF protein is completely absent. In addition to mucosal bleeding, patients may experience joint bleeds or central nervous system hemorrhage. Some physicians elect to treat patients with prophylaxis, or modified prophylaxis following injury, given that these patients typically have very low FVIII (<10 IU/dL). Laboratory Diagnosis There are no reliable screening tests for VWD. Patients with significant bleeding may present with anemia, and some patients with type 2B VWD and platelet-type pseudo-VWD may have thrombocytopenia. The partial thromboplastin time may be prolonged if FVIII is low but especially in type 1 VWD it is often normal, precluding use of the PTT as a screening test. Platelet function analysis has been considered as a screening test for VWD, but suboptimal sensitivity and specificity render results difficult to interpret. Bleeding times are similarly unreliable in diagnosis of VWD. No single test can reliably diagnose VWD ; these include VWF:Ag, which measures the total amount of VWF protein present, and VWF activity test, typically using the ristocetin cofactor activity assay (VWF:RCo ). VWF levels can be affected by external factors. Blood type has long been known to affect VWF, with lower VWF levels seen in people with blood group O. Stress, exercise, and pregnancy all increase VWF levels; therefore a single normal VWF level does not necessarily rule out the presence of VWD. Certain diseases, such as hypothyroidism , and medications, such as valproic acid, can lower VWF levels in affected patients. Repeat testing may be required to rule out or confirm a diagnosis of VWD. Treatment Treatment of VWD depends on the type of VWD present and the reason for treatment. In general, type 1 VWD patients may be treated with desmopressin , which increases the amount of circulating VWF by release from storage. Treatment of types 2 and 3 VWD requires VWF-containing concentrates similar to the treatment of hemophilia. For all types of VWD, adjunct therapy should be considered when possible, such as the use of antifibrinolytics for oral surgery or hormonal treatment for menorrhagia. Local treatment of epistaxis, such as nasal cautery or packing, may be helpful in some circumstances. Iron therapy for patients with iron-deficiency anemia may also be required.

Answer 36

Idiopathic (Autoimmune)Thrombocytopenic Purpura (ITP) The most common cause of acute onset of thrombocytopenia in an otherwise well child is idiopathic thrombocytopenic purpura (ITP ). Epidemiology : In one child from 20,000 child , 1-4 wk after exposure to a common viral infection, an autoantibody directed against the platelet surface develops with resultant sudden onset of thrombocytopenia. A recent history of viral illness is described in 50-65% of children with ITP. The peak age is 1-4 yr although the age ranges from early in infancy to elderly. In childhood, males and females are equally affected. Occur more often in late winter and spring after the peak season of viral respiratory illness. Pathogenesis : After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on splenic macrophages, ingested, and destroyed. Most common viruses have been described in association with ITP, including EpsteinBarr virus (EBV) and HIV. EBV-related ITP is usually of short duration and follows the course of infectious mononucleosis. HIV- associated ITP is usually chronic. In some patients, ITP appears to arise in children infected with Helicobacter pylori or rarely following vaccines. The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of generalized petechiae and purpura. The parents often say that their child was fine yesterday and now is covered with bruises and purple dots. Bleeding from the gums and mucous membranes, especially with profound thrombocytopenia (platelet count <10 × 109 /L). History of a preceding viral infection 1-4 wk before the onset of thrombocytopenia. Findings on physical examination are normal, other than petechia and purpura. Splenomegaly, lymphadenopathy, bone pain, and pallor are rare. The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain , remarkable lymphadenopathy other cytopenias , or congenital anomalies suggests other diagnoses (leukemia, syndromes). When the onset is insidious, especially in an adolescent, chronic ITP or the possibility of a systemic illness, such as systemic lupus erythematosus (SLE), is more likely. Outcome : Severe bleeding is rare (<3% of cases in 1 large international study). In 70–80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo. Therapy does not appear to affect the natural history of the illness. Less than 1% of patients develop an intracranial hemorrhage (ICH). The objective of early therapy is to raise the platelet count to >20 × 109 /L and prevent the rare development of ICH. There is no evidence that therapy prevents serious bleeding. 20% of children who present with acute ITP go on to have chronic ITP. The outcome/prognosis may be related more to age; ITP in younger children is more likely to resolve, whereas development of chronic ITP in adolescents approaches 50%. Laboratory Findings : CBP &ESR : Severe thrombocytopenia (platelet count <20 × 109 /L) is common, and platelet size is normal or increased, reflective of increased platelet turnover. In acute ITP the hemoglobin value, white blood cell (WBC) count, and differential count should be normal. Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia. Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes and some of the megakaryocytes may appear to be immature and reflect increased platelet turnover. Indications for bone marrow aspiration/biopsy: Abnormal WBC count or differential or unexplained anemia . History and physical examination findings suggestive of a bone marrow failure syndrome or malignancy Other laboratory tests should be performed as indicated by the history and examination. HIV studies should be done in at-risk populations, especially sexually active teens. Platelet antibody testing is seldom useful in acute ITP. Adirect antiglobulin test (Coombs) should be done if there is unexplained anemia , to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia). Evans syndrome may be idiopathic or an early sign of systemic lupus erythematosus, autoimmune lymphoproliferative syndrome or common variable immunodeficiency syndrome. An ANA should be considered in adolescents, especially with other features of SLE. Differential Diagnosis : Hemolytic-uremic syndrome (HUS) and disseminated intravascular coagulation (DIC) . Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, common variable immunodeficiency, and rarely, lymphoma or autoimmune lymphoproliferative syndrome. Wiskott-Aldrich syndrome must be considered in young males found to have thrombocytopenia with small platelets, particularly if there is a history of eczema and recurrent infection . Drugs : like heparin Valproic acid, Phenytoin, or sulfonamide trimethoprim Isolated enlargement of the spleen suggests the potential for hypersplenism caused by liver disease or portal vein thrombosis. Fanconi anemia and thethrombocytopenia–absent radius (TAR) syndrome . Treatment: There are no data showing that treatment affects either shortor long-term clinical outcome of ITP. Compared with untreated controls, treatment appears to induce a more rapid rise in platelet count to the safe level of >20 × 109 /L, although no data indicate that early therapy prevents ICH. Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets. Platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present. The management of ITP include the following: 1- Observation , education and counseling of the family are recommended for children with only mild bleeding symptoms such as bruising or petechiae . 2- Treatment with either IVIG or corticosteroids, particularly for children who present with mucocutaneous bleeding. A single dose of IVIG [intravenous immune globulin] (0.8-1.0 g/kg) or a short course of corticosteroids should be used as first-line treatment. IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days induces a rapid rise in platelet count (usually >20 × 109 /L) in 95% of patients within 48 hr. IVIG appears to induce a response by decreasing phagocytosis of antibody- coated platelets. IVIG therapy is both expensive and time-consuming to administer and after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis. Corticosteroid therapy has been used to treat acute and chronic ITP in adults and children. Doses of prednisone at 1-4 mg/kg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP. Corticosteroid therapy is usually continued for short course until a rise in platelet count to >20 × 109 /L has been achieved to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis. Each of these medications may be used to treat ITP exacerbations, which usually occur several weeks after an initial course of therapy. In ICH, multiple modalities should be used, including platelet transfusion, IVIG, high-dose corticosteroids, and prompt consultation by neurosurgery and surgery. There is no consensus regarding the management of acute childhood ITP, except that patients who are bleeding significantly (<5% of children with ITP)should be treated. Intracranial hemorrhage remains rare, and there are no data showing that treatment actually reduces its incidence. Mucosal bleeding in particular is the most significant in terms of predicting severe bleeding. Splenectomy should be reserved for 2 circumstances: (1) The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are not easily controlled with therapy . (2) When life-threatening hemorrhage (ICH) complicates acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids. Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms, increased risk of thrombosis, and the potential development of pulmonary hypertension in adulthood. As an alternative to splenectomy, rituximab has been used in children to treat chronic ITP. In 30–40% of children, rituximab has induced a partial or complete remission. Thrombopoietin receptor agonists have also been used to increase platelet count and are approved for pediatric use.

Answer 37

Chronic Autoimmune Thrombocytopenic Purpura : 20% of patients who present with acute ITP have persistent thrombocytopenia for >(6-12 mo ) ( chronic ITP ). Reevaluation for associated disorders should be performed, especially for autoimmune disease (SLE), chronic infectious disorders (HIV), and nonimmune causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, X-linked thrombocytopenia, autoimmune lymphoproliferative syndrome, common variable immunodeficiency syndrome, autosomal macrothrombocytopenia, and Wiskott-Aldrich syndrome (also X-linked). The presence of coexisting H. pylori infection should be considered and, if found, treated. Therapy should be aimed at controlling symptoms and preventing serious bleeding. Splenectomy : It is successful in inducing complete remission in 64–88% of children with chronic ITP. This effect must be balanced against the lifelong risk of overwhelming post splenectomy infection. This decision is often affected by quality-of-life issues, as well as the ease with which the child can be managed using medical therapy, such as IVIG, corticosteroids, IV anti-D, or rituximab. Two effective agnts that act to stimulate thrombopoiesis, romiplostim and eltrombopag, are approved by the U.S. Food and Drug Administration (FDA) to treat adults and children with chronic ITP. Although these do not address the mechanism of action of ITP, the increase in platelet count may be enough to compensate for the increased destruction and allow the patient to have resolution of bleeding and maintain a platelet count >50 × 109 /L.

Answer 38

Varicella-Zoster Virus Varicella-zoster virus (VZV) causes primary, latent, and recurrent infections. The primary infection is manifested as varicella (chickenpox) and results in establishment of a lifelong latent infection of sensory ganglion neurons. Reactivation of the latent infection causes herpes zoster (shingles). Although often a mild illness of childhood, varicella can cause substantial morbidity and mortality in otherwise healthy children. Morbidity and mortality are higher in immunocompetent infants, adolescents, and adults as well as in immunocompromised persons. Etiology: VZV is a neurotropic human herpesvirus with similarities to herpes simplex virus. Epidemiology: Most children were infected by 10 yr of age, with fewer than 5% of adults remaining susceptible. This pattern of infection at younger ages remains characteristic in all countries in temperate climates. Varicella is a more serious disease in young infants, adults, and immunocompromised persons, in whom there are higher rates of complications and deaths than in healthy children. Within households, transmission of VZV to susceptible individuals occurs at a rate of 65-86%; more casual contact, such as occurs in a school classroom, is associated with lower attack rates among susceptible children. Persons with varicella may be contagious 24-48 hr before the rash is evident and until vesicles are crusted, usually 3-7 days after onset of rash. Susceptible persons may also acquire varicella after close, direct contact with adults or children who have herpes zoster. Herpes zoster is caused by the reactivation of latent VZV. It is not common in childhood and shows no seasonal variation in incidence. Zoster is not caused by exposure to a patient with varicella; in fact, exposures to varicella boost the cellmediated immune response to VZV in individuals with prior infection, decreasing the likelihood of reactivation of latent virus. Herpes zoster in children tends to be milder than herpes zoster in adults, is less frequently associated with acute pain, and postherpetic neuralgia generally does not occur in healthy children. Pathogenesis: VZV is transmitted by contact with oropharyngeal secretions and the fluid of skin lesions of infected individuals, either by airborne spread or through direct contact. Primary infection (varicella) results from inoculation of the virus onto the mucosa of the upper respiratory tract and tonsillar lymphoid tissue. During the early part of the 10-21 day incubation period, virus replicates in the local lymphoid tissue, and spreads to T lymphocytes, causing a viremia that delivers the virus to skin where innate immunity controls VZV replication for some days. After innate immunity is overcome in skin, widespread cutaneous lesions develop as the incubation period ends. In the immunocompromised child, the failure of adaptive immunity, especially cellular immune responses, results in continued viral replication that may lead to prolonged and/or disseminated infection with resultant complications in the lungs, liver, brain, and other organs. The skin lesions of varicella and herpes zoster have identical histopathology, and infectious VZV is present in both.

Answer 39

Clinical Manifestations: Varicella in Unvaccinated Individuals: The illness usually begins 14-16 days after exposure, although the incubation period can range from 10-21 days. Subclinical varicella is rare; almost all exposed, susceptible persons experience a rash, albeit so mild in some cases that it may go unnoticed. Prodromal symptoms may be present, particularly in older children and adults. Fever, malaise, anorexia, headache, and occasionally mild abdominal pain may occur 24-48 hr before the rash appears. Temperature elevation is usually 37.8-38.9°C (100-102°F) but may be as high as 41.1°C (106°F); fever and other systemic symptoms usually resolve within 2-4 days after the onset of the rash. Varicella lesions often appear first on the scalp, face, or trunk. The initial exanthem consists of intensely pruritic erythematous macules that evolve through the papular stage to form clear, fluid-filled vesicles. Clouding and umbilication of the lesions begin in 24-48 hr. While the initial lesions are crusting, new crops form on the trunk and then the extremities; the simultaneous presence of lesions in various stages of evolution is characteristic of varicella. The distribution of the rash is predominantly central or centripetal with the greatest concentration on the trunk and proximally on the extremities. Ulcerative lesions involving the mucosa of the oropharynx and vagina are also common; many children have vesicular lesions on the eyelids and conjunctivae, but corneal involvement and serious ocular disease are rare. The exanthem may be much more extensive in children with skin disorders, such as eczema or recent sunburn. Hypopigmentation or hyperpigmentation of lesion sites persists for days to weeks in some children, but severe scarring is unusual unless the lesions were secondarily infected. Differential Diagnosis: + Herpes simplex + Enterovirus + Monkey pox + Rickettsial pox + Staph. Aureus + Drug reactions + Disseminated herpes simplex + Contact dermatitis + Insect bites Varicelliform Rashes in Vaccinated Individuals: Varicelliform rashes that occur after vaccination could be a result of wild-type VZV, vaccine strain VZV, or other etiologies (e.g., insect bites, coxsackievirus). In the early stages of a vaccine program, rash within 1-2 wk is still most commonly caused by wild-type VZV, reflecting exposure to varicella before vaccination could provide protection. Rash occurring 14-42 days after vaccination is a result of either wild-type or vaccine strains, reflecting exposure and infection before protection from vaccination or an adverse event of vaccination (vaccine-associated rash), respectively. Breakthrough varicella is disease that occurs in a person vaccinated more than 42 days before rash onset and is caused by wild-type virus. The rash in breakthrough disease is frequently atypical and predominantly maculopapular, vesicles are seen less commonly. The illness is most commonly mild with <50 lesions, shorter duration of rash, fewer complications, and little or no fever.

Answer 40

Neonatal Varicella: Mortality is particularly high in neonates born to susceptible mothers who contracted varicella around the time of delivery. Infants whose mothers demonstrate varicella in the period from 5 days prior to delivery to 2 days afterward are at high risk for severe varicella. These infants acquire the infection transplacentally as a result of maternal viremia, which may occur up to 48 hr prior to onset of maternal rash. The infant’s rash usually occurs toward the end of the 1st wk to the early part of the 2nd wk of life (although it may be as soon as 2 days). Newborns whose mothers develop varicella during the period of 5 days before to 2 days after delivery should receive VZIG as soon as possible. Although neonatal varicella may occur in about half of these infants despite administration of VZIG, it is usually milder than in the absence of VZIG administration. All premature infants born <28 wk of gestation to a mother with active varicella at delivery (even if the maternal rash has been present for >1 wk) should receive VZIG. Because perinatally acquired varicella may be life threatening, the infant should be treated with acyclovir (10 mg/kg every 8 hr IV) when lesions develop. Neonates with community-acquired varicella who experience severe varicella, especially those who have a complication such as pneumonia, hepatitis, or encephalitis, should also receive treatment with intravenous acyclovir (10 mg/kg every 8 hr). Infants with neonatal varicella who receive prompt antiviral therapy have an excellent prognosis.

Answer 41

Complications: # Asymptomatic transient varicella hepatitis( in otherwise healthy child) # Mild thrombocytopenia with petechiae # Progressive varicella # Acute cerebellar ataxia # Encephalitis # Pneumonia # Nephrotic syndrome, nephritis # HUS # Arthritis, myocarditis, pericarditis, pancreatitis, orchitis, and acute retinal necrosis. Bacterial Infections: Secondary bacterial infections of the skin, usually caused by group A Streptococcus and S. aureus, may occur in up to 5% of children with varicella. These range from impetigo to cellulitis, lymphadenitis, and subcutaneous abscesses. The more invasive infections, such as varicella gangrenosa, bacterial sepsis, pneumonia, arthritis, osteomyelitis, cellulitis, and necrotizing fasciitis, account for much of the morbidity and mortality of varicella in otherwise healthy children.

Answer 42

Diagnosis: o Varicella and herpes zoster have been diagnosed primarily by their clinical appearance. o Leukopenia is typical during the 1st 72 hr after onset of rash; it is followed by a relative and absolute lymphocytosis. o Results of liver function tests are also usually (75%) mildly elevated. o Direct fluorescence assay of cells from cutaneous lesions (vesicular fluid) in 15-20 min, by PCR amplification testing (vesicular fluid, crusts) o Rapid culture with specific immunofluorescence staining o Scrapings of maculopapular lesions can be collected for PCR or direct fluorescence assay testing. o PCR is the most sensitive and allows for differentiation of wild-type and vaccine strains. o A 4-fold or greater rise in IgG antibodies is confirmatory of acute infection. Treatment: Varicella: The only antiviral drug available in liquid formulation that is licensed for treatment of varicella for pediatric use is acyclovir. However, acyclovir therapy is not recommended routinely by the American Academy of Pediatrics for treatment of uncomplicated varicella in the otherwise healthy child because of the marginal benefit, the cost of the drug, and the low risk for complications of varicella. Oral therapy with acyclovir (20 mg/kg/dose; maximum: 800 mg/dose) given as 4 doses/day for 5 days can be used to treat uncomplicated varicella in individuals at increased risk for moderate to severe varicella: nonpregnant individuals older than 12 yr of age and individuals older than 12 mo of age with chronic cutaneous or pulmonary disorders; individuals receiving short-term, intermittent, or aerosolized corticosteroid therapy; individuals receiving longterm salicylate therapy; and possibly secondary cases among household contacts. To be most effective, treatment should be initiated as early as possible, preferably within 24 hr of the onset of the exanthem. There is less clinical benefit if treatment is initiated more than 72 hr after onset of the exanthema. Some experts recommend the use of famciclovir or valacyclovir in older children who can swallow tablets. Intravenous therapy is indicated for severe disease and for varicella in immunocompromised patients (even if begun more than 72 hr after onset of rash). Any patient who has signs of disseminated VZV, including pneumonia, severe hepatitis, thrombocytopenia, or encephalitis, should receive immediate treatment. IV acyclovir therapy (500 mg/m2 every 8 hr) initiated within 72 hr of development of initial symptoms decreases the likelihood of progressive varicella and visceral dissemination in high-risk patients. Treatment is continued for 7-10 days or until no new lesions have appeared for 48 hr. Acyclovir-resistant VZV has been identified primarily in children infected with HIV. These children may be treated with intravenous foscarnet (120 mg/kg/day divided every 8 hr for up to 3 wk).

Answer 43

Herpes Zoster: Treatment of uncomplicated herpes zoster in the child with an antiviral agent may not always be necessary, treatment with oral acyclovir (20 mg/kg/dose; maximum: 800 mg/dose) to shorten the duration of the illness(start antiviral therapy as soon as possible, delay beyond 72 hr from onset of rash limits its effectiveness). Patients at high risk for disseminated disease should receive IV acyclovir (500 mg/ m2 or 10 mg/kg every 8 hr. Use of corticosteroids in the treatment of herpes zoster in children is not recommended. Prognosis: Primary varicella has a mortality rate of 2-3 per 100,000 cases, with the lowest case fatality rates among children 1-9 yr of age. Compared with these age groups, infants have a 4 times greater risk of dying and adults have a 25 times greater risk of dying. Herpes zoster among healthy children has an excellent prognosis and is usually selflimited. Severe presentation with complications and sometimes fatalities can occur in immunocompromised children. Prevention: VZV transmission is difficult to prevent, especially from persons with varicella, because a person with varicella is contagious for 24-48 hr before the rash is apparent. Vaccine: Varicella is a vaccine-preventable disease. Varicella vaccine contains live, attenuated VZV and is indicated for subcutaneous administration. Varicella vaccine is safe and well tolerated. In the United States, varicella vaccine is recommended for routine administration as a 2 dose regimen. Vaccination with 2 doses is recommended for all persons without evidence of immunity. The minimum interval between the 2 doses is 3 mo for persons 12 yr of age or younger and 4 wk for older children, adolescents, and adults. Postexposure Prophylaxis: = Vaccine given to healthy children within 3 or 5 days after exposure (as soon as possible is preferred) is effective in preventing or modifying varicella. = Oral acyclovir administered late in the incubation period may modify subsequent varicella in the healthy child; however, its use in this manner is not recommended until it can be further evaluated. = High-titer anti-VZV immune globulin as postexposure prophylaxis is recommended for immunocompromised children, pregnant women, and newborns exposed to varicella.

Answer 44

Leishmaniasis The leishmaniases are a diverse group of diseases caused by intracellular protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sand flies. Multiple species of Leishmania are known to cause human disease involving the skin and mucosal surfaces and the visceral reticuloendothelial organs. Cutaneous disease is generally mild but may cause cosmetic disfigurement. Mucosal and visceral leishmaniasis is associated with significant morbidity and mortality. Etiology Leishmania organisms are members of the Trypanosomatidae family and include 2 subgenera, Leishmania (Leishmania) and Leishmania (Viannia). The parasite is dimorphic, existing as a flagellate promastigote in the insect vector and as an aflagellate amastigote that resides and replicates within mononuclear phagocytes of the vertebrate host. Epidemiology The leishmaniases are estimated to affect 10-20 million people in endemic tropical and subtropical regions on all continents except Australia and Antarctica. With only rare exceptions, the Leishmania organisms that primarily cause cutaneous disease do not cause visceral disease. The emergence of the leishmaniases in new areas is the result of (1) movement of a susceptible population into existing endemic areas, usually because of agricultural or industrial development or timber harvesting; (2) increase in vector and/or reservoir populations as a result of agriculture development projects or climate change; (3) increase in anthroponotic transmission owing to rapid urbanization in some focuses; and (4) increase in sandfly density resulting from a reduction in vector control programs. Pathology Histopathologic analysis of the Localized cutaneous leishmaniasis (LCL) and disseminated leishmaniasis (DL) lesion shows intense chronic granulomatous inflammation involving the epidermis and dermis with relatively few amastigotes. Occasionally, neutrophils and even microabscesses can be seen. In Visceral leishmaniasis (VL) there is prominent reticuloendothelial cell hyperplasia in the liver, spleen, bone marrow, and lymph nodes. Amastigotes are abundant in the histiocytes and Kupffer cells. Late in the course of disease, splenic infarcts are common, centrilobular necrosis and fatty infiltration of the liver occur, the normal marrow elements are replaced by parasitized histiocytes, and erythrophagocytosis is present. Pathogenesis Cellular immune mechanisms determine resistance or susceptibility to infection with Leishmania. Resistance is mediated by interleukin(IL)-12 driven generation of a T helper 1 cell response, with interferon-γ inducing classical macrophage (M1) activation and parasite killing. Within endemic areas, people who have had a subclinical infection can be identified by a positive delayed-type hypersensitivity skin response to leishmanial antigens (Montenegro skin test) or by antigen-induced production of interferon-γ in a whole blood assay. Subclinical infection occurs considerably more frequently than does active cutaneous or visceral disease. Individuals with prior activedisease or subclinical infection are usually immune to a subsequent clinical infection; however, latent infection can lead to active disease if the patient is immunosuppressed.

Answer 45

Clinical Manifestations Visceral Leishmaniasis: VL (kala-azar) typically affects children < 5 yr of age in the New World and Mediterranean region (L. infantum/chagasi) and older children and young adults in Africa and Asia (L. donovani). After inoculation of the organism into the skin by the sandfly, the child may have a completely asymptomatic infection or an oligosymptomatic illness that either resolves spontaneously or evolves into active kala-azar. Children with asymptomatic infection are transiently seropositive but show no clinical evidence of disease. Children who are oligosymptomatic have mild constitutional symptoms (malaise, intermittent diarrhea, poor activity tolerance) and intermittent fever; most will have a mildly enlarged liver. In most of these children the illness will resolve without therapy, but in approximately 25% it will evolve to active kala-azar within 2-8 mo. Extreme incubation periods of several years have rarely been described. During the first few wk to months of disease evolution the fever is intermittent, there is weakness and loss of energy and the spleen begins to enlarge. The classic clinical features of high fever, marked splenomegaly, hepatomegaly, and severe cachexia typically develop 3-6 mo after the onset of the illness, but a rapid clinical course over 1 mo has been noted in up to 20% of patients in some series. At the terminal stages of kala-azar the hepatosplenomegaly is massive, there is gross wasting, the pancytopenia is profound, and jaundice, edema, and ascites may be present. Anemia may be severe enough to precipitate heart failure. Bleeding episodes, especially epistaxis, are frequent. The late stage of the illness is often complicated by secondary bacterial infections, which frequently are a cause of death. A younger age at the time of infection, HIV co-infection, and underlying malnutrition may be risk factors for the development and more rapid evolution of active VL. Death occurs in > 90% of patients without specific antileishmanial treatment and in 4-10% of treated patients. Leishmaniasis may also result from reactivation of a longstanding subclinical infection. Frequently there is an atypical clinical presentation of VL in HIV-infected individuals with prominent involvement of the gastrointestinal tract and absence of the typical hepatosplenomegaly. Laboratory findings Laboratory findings associated with classic kala-azar include anemia (hemoglobin 5-8 mg/dL), thrombocytopenia, leukopenia (2,000-3,000 cells/μL), elevated hepatic transaminase levels, and hyperglobulinemia (>5 g/dL) that is mostly immunoglobulin G. Differential diagnosis malaria, typhoid fever, miliary tuberculosis, schistosomiasis, brucellosis, amebic liver abscess, infectious mononucleosis, lymphoma, andleukemia. Diagnosis Serologic testing by enzyme immunoassay, indirect fluorescence assay, or direct agglutination is very useful in VL because of the very high level of antileishmanial antibodies. An immunochromatographic strip test using a recombinant antigen (K39) has a diagnostic sensitivity and specificity for VL of 80-90% and 95%, respectively. Serodiagnostic tests have positive findings in only about half of the patients who are co-infected with HIV. Definitive diagnosis of leishmaniasis is established by the demonstration of amastigotes in tissue specimens or isolation of the organism by culture. In patients with VL, smears or cultures (by using Novy-McNeal-Nicolle (NNN) biphasic blood agar medium ) of material from splenic, bone marrow, or lymph node aspirations are usually diagnostic. Treatment All patients with VL should receive therapy. The pentavalent antimony compounds (sodium stibogluconate (Pentostam,)and meglumine antimoniate have been the mainstay of antileishmanial chemotherapy for >40 yr. These drugs have similar efficacies, toxicities, and treatment regimens. the recommended regimen is 20 mg/kg/day intravenously or intramuscularly for 28 days. An initial clinical response to therapy usually occurs in the 1st wk of therapy, but complete clinical healing ( regression of splenomegaly and normalization of cytopenias ) is usually not evident for weeks to a few months after completion of therapy. Cure rates with this regimen 80-100% for VL were common in the 1990s, but clinical resistance to antimony therapy has become common. Adverse effects of antimony therapy are dose and duration dependent and commonly include fatigue, arthralgias and myalgias (50%), abdominal discomfort (30%), elevated hepatic transaminase level (30-80%), elevated amylase and lipase levels (almost 100%), mild hematologic changes (slightly decreased leukocyte count, hemoglobin level, and platelet count) (10-30%), and nonspecific T-wave changes on electrocardiography (30%). Sudden death due to cardiac toxicity is extremely rare and is usually associated with use of very high doses of pentavalent antimony. Amphotericin B desoxycholate at doses of 0.5-1.0 mg/kg every day or every other day for 14-20 doses achieved a cure rate for VL of close to 100%, but the renal toxicity associated with amphotericin B was common. Aminoglycoside paromomycin (aminosidine) has efficacy (∼95%) similar to that of amphotericin B. Miltefosine, a membrane-activating alkylphospholipid 50-100 mg/day for 28 days, has been recently developed as the 1st oral treatment for VL and has a cure rate of 95% . needed, especially in children. Prevention Personal protective measures should include avoidance of exposure to the nocturnal sandflies and, when necessary, the use of insect repellent and permethrin-impregnated mosquito netting. Where peridomiciliary transmission is present, community-based residual insecticide spraying has had some success in reducing the prevalence of leishmaniasis, but long-term effects are difficult to maintain. Control or elimination of infected reservoir hosts (e.g., seropositive domestic dogs) has had limited success. Where anthroponotic transmission is thought to occur, early recognition and treatment of cases are essential. Several vaccines have been demonstrated to have efficacy in experimental models, and vaccination of humans or domestic dogs may have a role in the control of the leishmaniases in the future.

Answer 46

Pertussis (Bordetella pertussis and B. parapertussis) Bordetella organisms are small, fastidious, gram-negative coccobacilli. Bordetella pertussis is the sole cause of epidemic pertussis and the usual cause of sporadic pertussis. B. parapertussis is an occasional cause of pertussis. B. pertussis and B. parapertussis are exclusive pathogens of humans. B. bronchiseptica is a common animal pathogen. Pertussis is extremely contagious, with attack rates as high as 100% in susceptible individuals exposed to aerosol droplets at close range. Neither natural disease nor vaccination provides complete or lifelong immunity against reinfection or disease. Clinical Manifestations Classically, pertussis is a prolonged disease, divided into catarrhal, paroxysmal, and convalescent stages. The catarrhal stage (1-2 wk) begins insidiously after an incubation period ranging from 3-12 days with nondistinctive symptoms of congestion and rhinorrhea. As initial symptoms wane, coughing marks the onset of the paroxysmal stage (2-6 wk). The cough begins as a dry, intermittent, irritative hack and evolves into the inexorable paroxysms that are the hallmark of pertussis. A well-appearing, playful toddler with insignificant provocation suddenly expresses an anxious aura and may clutch a parent or comforting adult before beginning a machine-gun burst of uninterrupted cough on a single exhalation, chin and chest held forward, tongue protruding maximally, eyes bulging and watering, face purple, until coughing ceases and a loud whoop follows as inspired air traverses the still partially closed airway. Post-tussive emesis is common, and exhaustion is universal. The number and severity of paroxysms escalate over days to a week and remain at that plateau for days to weeks. At the peak of the paroxysmal stage, patients may have more than 1 episode hourly. As the paroxysmal stage fades into the convalescent stage (≥2 wk), the number, severity, and duration of episodes diminish.{Protracted coughing (which in some cases is paroxysmal) is attributable sporadically to Mycoplasma, parainfluenza viruses, influenza viruses, enteroviruses, respiratory syncytial virus (RSV), or adenoviruses. Infants <3 mo of age do not display the classic stages. The catarrhal phase lasts only a few days or is unnoticed, and then, after the most insignificant startle from a draft, light, sound, sucking, or stretching, a well-appearing young infant begins to choke, gasp, gag, and flail the extremities, with face reddened. Cough may not be prominent, especially in the early phase. Whoop infrequently occurs in infants <3 mo of age who at the end of a paroxysm lack stature or muscular strength to create sudden negative intrathoracic pressure. Apnea and cyanosis can follow a coughing paroxysm, or apnea can occur without a cough as the only symptom. Apnea and cyanosis both are more common with pertussis than with neonat al viral infections. The paroxysmal and convalescent stages in young infants are lengthy. Paradoxically, in infants, cough and whooping may become louder and more classic in convalescence. “Exacerbations” of paroxysmal coughing can occur throughout the first year of life with subsequent respiratory illnesses; these are not a result of recurrent infection or reactivation of B. pertussis. Adolescents and previously immunized children have foreshortening of all stages of pertussis. Adults have no distinct stages. Classically, adolescents and adults describe a sudden feeling of strangulation followed by uninterrupted coughs, feeling of suffocation, bursting headache, diminished awareness, and then a gasping breath, usually without a whoop. Post-tussive emesis and intermittency of paroxysms separated by hours of well-being are specific clues to the diagnosis in adolescents and adults. At least 30% of older individuals with pertussis have nonspecific cough illness, distinguished only by duration, which is usually >21 days. Findings on physical examination generally are uninformative. Signs of lower respiratory tract disease are not expected unless complicating secondary bacterial pneumonia is present. Conjunctival hemorrhages and petechiae on the upper body are common.

Answer 47

Diagnosis Pertussis should be suspected in any individual who has pure or predominant complaint of cough, especially if the following are absent: fever, malaise or myalgia, exanthem or enanthem, sore throat, hoarseness, tachypnea, wheezes, and rales. Leukocytosis (15,000–100,000 cells/mm3 ) due to absolute lymphocytosis is characteristic in the catarrhal stage. Absolute increase in neutrophils suggests a different diagnosis or secondary bacterial infection. The chest radiograph appearance is mildly abnormal in the majority of hospitalized infants. Parenchymal consolidation suggests secondary bacterial infection. Pneumothorax, pneumomediastinum, and subcutaneous emphysema can be seen occasionally. Isolation of B. pertussis in culture remains the gold standard for diagnosis. PCR testing on nasopharyngeal wash specimens is the lab.test of choice for B.pertussis identification. Treatment Infants < 3 mo are usually hospitalized, as are many 3-6 mo old, unless witnessed paroxysms are not severe, and at any age if significant complications occur. Prematurely born young infants and children with underlying cardiac, pulmonary, muscular, or neurologic disorders have a high risk for severe disease. Typical paroxysms that are not life threatening have the following features: a) duration less than 45 sec; b) red but not blue color change; c) tachycardia, bradycardia (not <60 beats/min in infants), or oxygen desaturation that spontaneously resolves at the end of the paroxysm; d) whooping or strength for self-rescue at the end of the paroxysm; e) Self-expectorated mucus plug; and f) post-tussive exhaustion but not unresponsiveness. Hospital discharge is appropriate if over a 48 hr period disease severity is unchanged or diminished, no intervention is required during paroxysms, nutrition is adequate, no complication has occurred, and parents are adequately prepared for care at home.

Answer 48

Antimicrobial agents An antimicrobial agent is always given when pertussis is suspected or confirmed to decrease contagiousnous and to afford possible clinical benefit. Azithromycin (10 mg/kg/day in a single dose for day1, then 5 mg/kg/day on days 2-5) is the drug of choice in all age-groups for postexposure prophylaxis. Erythromycin (40-50mg/kg/24hr divided qid PO; maximum: 2g/24hr) for 14 days can be used, although not preferred in neonatal period(IHPS). Clarithromycin also can be used. Trimethoprim-sulfamethoxazole (TMP-SMX) is an alternative to azithromycin for infants >2 mo old and children unable to receive azithromycin. Patients are placed in respiratory isolation for 5 days after initiation of azitthromycin therapy. Care of Household and Other Close Contacts Macrolide agent should be given promptly to all household contacts and other close contacts, such as those in daycare, regardless of age, history of immunization, or symptoms. Close contacts <7 yr of age who have received less than four doses of pertussis-containing vaccines should have vaccination initiated or continued to complete the recommended series. Complications The principal complications of pertussis are apnea, secondary infections, expected pathogens include Staphylococcus aureus, S. pneumoniae, and bacteria of oropharyngeal flora, (such as otitis media and pneumonia), and physical sequelae of forceful coughing. Bronchiectasis has been reported rarely after pertussis. Increased intrathoracic and intra-abdominal pressure during coughing can result in conjunctival and scleral hemorrhages, petechiae on the upper body, epistaxis, hemorrhage in the central nervous system (CNS) and retina, pneumothorax and subcutaneous emphysema, and umbilical and inguinal hernias. Laceration of the lingual frenulum is not uncommon. Rectal prolapse is distinctly unusual and should elicit evaluation for underlying condition. Especially in infants in developing countries, dehydration and malnutrition following post-tussive vomiting can have a severe impact. Tetany has been associated with profound post-tussive alkalosis. CNS abnormalities occur at a relatively high frequency and are almost always a result of hypoxemia or hemorrhage associated with coughing or apnea in young infants. Apnea or bradycardia or both may result from apparent laryngospasm or vagal stimulation just before a coughing episode, from obstruction during an episode, or from hypoxemia following an episode. Lack of associated respiratory signs in some young infants with apnea raises the possibility of a primary effect of PT on the CNS. Seizures are usually a result of hypoxemia, but hyponatremia from excessive secretion of antidiuretic hormone during pneumonia can occur.

Answer 49

Tuberculosis has caused human disease for more than 4,000 yr & is one of the most important infectious diseases worldwide. Etiology:. There are 5 closely related mycobacteria in the M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti. M. tuberculosis is the most important cause of tuberculosis disease in humans. The tubercle bacilli are non–spore-forming, nonmotile, pleomorphic, weakly gram-positive curved rods that are obligate aerobes & grow in synthetic media containing glycerol as the carbon source and ammonium salts as the nitrogen source (Loewenstein-Jensen culture media) & have a lipid-rich cell wall that accounts for resistance to the bactericidal actions of antibody and complement. A hallmark of all mycobacteria is acid fastness—the capacity to form stable mycolate complexes. Isolation from clinical specimens on solid synthetic media usually takes 3-6 wk, and drug susceptibility testing requires an additional 2- 4 wk. Terminology: Exposure, Infection, Disease Exposure: means a child has significant contact with an adult or adolescent with infectious tuberculosis but lacks proof of infection. The tuberculin skin test (TST) or interferon-γ release assay (IGRA) is –ve, CXR—normal, physical exam.—normal, & the child has no signs & symptoms. Infection: the individual inhales droplet nuclei containing M.tuberculosis, which survive intracellularly within the lung & associated lymphoid tissue. TST or IGRA is +ve, no s & s, exam.—normal, CXR—normal or reveals only granuloma or calcifications in the lung parenchyma. Disease: S & s or CXR manifestations become apparent. Epidemiolopgy: *The WHO estimates that TB remains the 2 nd leading cause of death form an infectious disease(after HIV). *1/3 of the world‘s population are infected with TB. *The global burden of TB is influenced by several factors including: the HIV pandemic, the development of multidrug resistant (MDR)TB, & the disproportionate access of populations to both diagnostic tests & effective medical therapy. *Among adults, two-thirds of cases occur in men, but in children there is no significant difference by gender. * Specific groups are at high risk for acquiring tuberculosis infection and progressing from latent tuberculosis infection (LTBI) to tuberculosis. *The estimate for MDR tuberculosis is 4% globally.}MDR-TB is defined as resistance to at least isoniazid and rifampin; extensively drug -resistant tuberculosis includes MDR-TB plus resistance to any fluoroquinolone and at least 1 of 3 injectable drugs (kanamycin, capreomycin, amikacin){. Transmission: ** By inhalation of airborne mucus droplet nuclei that contain M.tuberculosis. **Rarely occurs by direct contact with an infected discharge or a contaminated fomite. **The chance of transmission increases when the patient has: a positive acid-fast smear of sputum, an extensive upper lobe infiltrate or cavity, copious production of thin sputum, severe and forceful cough, environmental factors such as poor air circulation. **Most adults no longer transmit the organism within several days to 2 wks after beginning adequate chemotherapy, but some remain infectious for many weeks. Young children with TB rarely infect other children or adults(Tubercle bacilli are sparse in the endobronchial secretions of children, and cough is often absent or lacks the tussive force required to suspend infectious particles of the correct size).

Answer 50

Risk Factors For TB Infection:  Children exposed to high-risk adults  Foreign-born persons from high-prevalence countries  Homeless persons  Persons who inject drugs  Present and former residents or employees of correctional institutions, homeless shelters, and nursing homes  Healthcare workers caring for high-risk patients (if infection control is not adequate). Risk Factors For Drug-Resistant Tuberculosis  Personal or contact history of treatment for tuberculosis  Contacts of patients with drug-resistant tuberculosis  Birth or residence in a country with a high rate of drug resistance  Poor response to standard therapy  Positive sputum smears (acid-fast bacilli) or culture ≥2 mo after appropriate therapy initiating Pathogenesis:# The primary complex (or Ghon complex) of tuberculosis includes local infection at the portal of entry and the regional lymph nodes that drain the area. The lung is the portal of entry in >98% of cases, where most of bacilli are killed, but some survive within nonactivated macrophages, then through lymphatics to regional LN. # The tissue reaction in the parenchyma & LN intensifies over 2-12wk (cell-mediated immunity). # The parenchymal primary complex heals completely by fibrosis or calcification after undergoing caseous necrosis & encapsulation. If caseation is intense, the center of the lesion liquefies leaving a residual cavity. # Partial obstruction of the bronchus caused by external compression can cause hyperinflation in the distal lung segment. Complete obstruction results in atelectasis. Inflamed caseous nodes can attach to the bronchial wall and erode through it, causing endobronchial tuberculosis or a fistula tract. The caseum causes complete obstruction of the bronchus. The resulting lesion is a combination of pneumonitis and atelectasis and has been called a collapse-consolidation or segmental lesion. # During the development of Ghon Complex, TB bacilli are carried by blood an d lymph. vessels to most tissues , replication is more in lung apices , brain , kidneys, and bones due to high blood and O2 supply. # Disseminated tuberculosis occurs if the number of circulating bacilli is large and the host’s cellular immune response is inadequate. More often the number of bacilli is small, leading to clinically inapparent metastatic foci in many organs. # Disseminated and meningeal tuberculosis are early manifestations, often occurring within 2-6 mo of acquisition. Significant lymph node or endobronchial tuberculosis usually appears within 3-9 mo. Lesions of the bones and joints take several years to develop, whereas renal lesions become evident decades after infection. Extrapulmonary manifestations are more common in children than adults and develop in 25-35% of children with tuberculosis, compared to approximately 10% of immunocompetent adults.

Answer 51

Clinical Manifestation: Primary Pulmonary Disease: The primary complex includes the parenchymal pulmonary focus and the regional lymph nodes. The hallmark of primary tuberculosis in the lung is the relatively large size of the regional lymphadenitis compared with the relatively small size of the initial lung focus. Hilar LAP—compression the regional bronchus---obstruction. Hilar LAP—focal hyperinflation—atelectasis (CXR shows collapse-consolidation or segmental tuberculosis. Subcarinal LAP—compression of the esophagus—bronchoesophageal fistula. The appearance of calcification implies that the lesion has been present for at least 6-12 mo. If the primary infection is progressively destructive, liquefaction of the lung parenchyma can lead to formation of a thin-walled primary tuberculosis cavity. Erosion of a parenchymal focus of tuberculosis into a blood or lymphatic vessel can result in dissemination of the bacilli and a miliary pattern.  Up to 50% of infants and children with radiographically moderate to severe pulmonary tuberculosis have no physical findings.  Infants are more likely to experience signs and symptoms. Nonproductive cough and mild dyspnea are the most common symptoms.  Systemic complaints such as fever, night sweats, anorexia, and decreased activity occur less often.  Difficulty gaining weight or develop a true failure-to-thrive syndrome that often does not improve significantly until several months of effective treatment.  Pulmonary signs are even less common. Some infants and young children with bronchial obstruction have localized wheezing or decreased breath sounds that may be accompanied by tachypnea or, rarely, respiratory distress. Progressive Primary Pulm. TB: Progressive enlargement of primary focus with large caseous centre  cavitation with large no. of TB bacilli which slough necrotic debris into adjacent bronchus  severe productive cough with high fever, night sweats and weigh loss, with and dullness. Pleural Effusion: breath sounds Asymptomatic local pleural effusion is so common in primary tuberculosis. Larger and clinically significant effusions occur months to years after the primary infection. Tuberculous pleural effusion is uncommon in children younger than 6 yr of age and rare in children younger than 2 yr of age. Effusions are usually unilateral but can be bilateral. Clinical onset of tuberculous pleurisy is often sudden, characterized by low to high fever, shortness of breath, chest pain on deep inspiration, and diminished breath sounds. Dx.:  CXR: shows abnormality more extensive than signs and symptoms.  The TST is positive in only 70-80% of cases.  The pleural fluid:( yellow and only occasionally tinged with blood, SpG 1.012- 1.025, the protein 2-4 g/dL, glucose may be low, although it is usually in the low-normal range (20-40 mg/dL), several hundred to several thousand WBC per microliter, with an early predominance of polymorphonuclear cells followed by a high percentage of lymphocytes, AFB are rarely positive, cultures are positive in <30% of cases).  Biopsy of the pleural membrane is more likely to yield a positive acid-fast stain or culture, and granuloma formation can be demonstrated. Lymphohematogenous (Disseminated) Disease: Tubercle bacilli are disseminated to distant sites, including liver, spleen, skin, and lung apices, in all cases of tuberculosis infection. The clinical picture may be acute, more often it is prolonged, with spiking fever accompanying the release of organisms into the bloodstream. Multiple organ involvement is common, leading to hepatomegaly, splenomegaly, lymphadenitis in superficial or deep nodes, and papulonecrotic tuberculids appearing on the skin. Bones and joints or kidneys also can become involved. Meningitis occurs only late in the course of the disease. The most clinically significant form of disseminated tuberculosis is miliary disease, which occurs when massive numbers of tubercle bacilli are released into the bloodstream(most common in infants and malnourished or immunosuppressed patients) causing disease in 2 or more organs(within 2-6months). More often, the onset is insidious, with early systemic signs, including anorexia, weight loss, and low-grade fever. At this time, abnormal physical signs are usually absent. Generalized lymphadenopathy and hepatosplenomegaly develop within several weeks in approximately 50% of cases. Within several more weeks, the lungs can become filled with tubercles, and dyspnea, cough, rales, or wheezing occur. Signs or symptoms of meningitis or peritonitis are found in 20-40% of patients with advanced disease. Chronic or recurrent headache in a patient with miliary tuberculosis usually indicates the presence of meningitis, whereas the onset of abdominal pain or tenderness is a sign of tuberculous peritonitis. Dx.: *The most important clue is usually history of recent exposure to an adult with infectious tuberculosis. *TST is nonreactive in up to 40% of patients. *Early sputum or gastric aspirate cultures have a low sensitivity. *Biopsy of the liver or bone marrow with appropriate bacteriologic and histologic examinations more often yields an early diagnosis. *CXR : diffuse 2- 3 mm. lesions which then coalesce to form extensive infiltrates  "alveolar – air block syndrome "  severe SOB , hypoxia and pneumothorax. *" Choroid tubercles " are highly specific for diagnosis of miliary TB. CNS Disease: Tuberculous meningitis complicates approximately 0.3% of untreated tuberculosis infections in children( common between 6 mo and 4 yr of age), occasionally many years after the infection, when rupture of 1 or more of the subependymal tubercles discharges tubercle bacilli into the subarachnoid space. Rapid progression tends to occur more often in infants and young children, who can experience symptoms for only several days before the onset of acute hydrocephalus, seizures, and cerebral edema. More commonly, the signs and symptoms progress slowly over weeks and are divided into 3 stages: 1 st stage: typically lasts 1-2 wk, nonspecific symptoms such as fever, headache, irritability, drowsiness, and malaise, or loss of developmental milestones. Focal neurologic signs are absent. 2 nd stage: more abrupt, lethargy, nuchal rigidity, seizures, positive Kernig and Brudzinski signs, hypertonia, vomiting, and cranial nerve palsies. 3 rd stage: coma, hemi- or paraplegia, hypertension, decerebrate posturing, deterioration of vital signs, and eventually death. The majority of patients in the 1 st stage have an excellent outcome, whereas most patients in the 3 rd stage who survive have permanent disabilities, including blindness, deafness, paraplegia, diabetes insipidus, or mental retardation. Another manifestation of CNS tuberculosis is the tuberculoma, a tumor-like mass resulting from aggregation of caseous tubercles that usually manifests clinically as a brain tumor.

Answer 52

Perinatal Disease: Symptoms of congenital tuberculosis may be present at birth but more commonly begin by the 2nd or 3rd wk of life. The most common signs and symptoms are respiratory distress, fever, hepatic or splenic enlargement, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, failure to thrive, ear drainage, and skin lesions. Hilar and mediastinal lymphadenopathy and lung infiltrates are common. Generalized lymphadenopathy and meningitis occur in 30-50% of patients. Dx. # TST is negative initially but can become positive in 1-3 mo. # A +ve AFB of an early morning gastric aspirate. # Direct AFB on middle-ear discharge, bone marrow, tracheal aspirate, or biopsy tissue (especially liver). # CSF culture and PCR testing.

Answer 53

Dx. *CSF exam. : WBC count 10-500cells/µL predominantly lymphocytes, CSF glucose<40 mg/dL, protein is markedly 400-5,000mg/dL, AFB+ve in 30%, culture +ve in 50-70%, CSF PCR improve the dx.*TST is nonreactive in up to 50% *CXR is normal in 20-50% *Cultures of other body fluids can help confirm dx.*CT or MRI. Diagnostic Tools For TB: I-Mantoux TST: is the i.d. injection of 0.1 mL purified protein derivative that induces induration through local vasodilation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area. The amount of induration in response to the test should be measured by a trained person 48-72 hr after administration., the onset of induration of longer than 72 hr after placement is also a positive result. Immediate hypersensitivity reactions to tuberculin or other constituents of the preparation are short-lived (<24 hr) and not considered a positive result. Tuberculin sensitivity develops 3 wk to 3 mo (most often in 4-8 wk) after inhalation of organisms. Factors that affect the TST result:  Very young age  Malnutrition  Immunosuppression (by drugs or disease)  Viral infection (measles, mumps, varicella, influenza)  Vaccination with live-virus vaccines  Overwhelming TB  Corticosteroid therapy. False-positive reactions to tuberculin can be caused by cross-sensitization to antigens of nontuberculous Mycobacterium. Definitions of +ve TST in infants, children, & adolescents: 1.Induration ≥5 mm Children in close contact with known or suspected contagious people with TB Children suspected to have TB: • Findings on chest radiograph consistent with active or previous TB • Clinical evidence of TB Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection. 2. Induration ≥10 mm Children at increased risk of disseminated tuberculosis disease: • Children younger than 4 yr of age • Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, or malnutrition. Children with increased exposure to tuberculosis disease: • Children born in high-prevalence regions of the world • Children often exposed to adults who are HIV infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized, or migrant farm workers • Children who travel to high-prevalence regions of the world. 3. Induration ≥15 mm: Children ≥4 yr of age without any risk factors. II- Interfaron-γ Release Assay (IGRA): measures whole blood concentrations of INFγ & the number of lymphocytes/monocytes producing INF-γ. Two clear advantages of the IGRAs are the need for only 1 patient encounter (vs 2 with the TST) and the lack of crossreaction with BCG vaccination and most other mycobacteria. III- Nucleic Acid Amplification: the main form is PCR, which uses specific DNA sequences as markers for microorganisms. A negative PCR result never eliminates the diagnosis of tuberculosis, and the diagnosis is not confirmed by a positive PCR result. Mycobacterial Sampling,Susceptibility And Culture: Pulmonary TB: isolation of M. tuberculosis from a clinical sample. Sputum (for AFB & culture) should be collected from adolescents and older children who are able to expectorate. Induced sputum with a jet nebulizer, inhaled saline and chest percussion followed by nasopharyngeal suctioning is effective in children as young as 1 yr of age. The traditional culture specimen in young children is the early morning gastric acid obtained (3 consecutive morning gastric aspirates yield the organisms in <50% of cases). Extrapulmonary TB: +ve culture (only in25-50%) with combination of clinical signs & symptoms, analysis of body fluids, radiographic or histopathlogic evidence of TB, & elimination of other possible causes.

Answer 54

Treatment: These infections require therapy with multiple agents, yet, they have complex drug resistance , and patients often have underlying conditions which affect drug choice and monitoring . Commonly Used Agents : 1) Isoniazid ( INH ) : an isonicotinic acid derivative , is bactericidal for cell wall production. Dose : 10-15 mg/kg/day PO as a single dose 1h. before or 2h. after meal. S.E. : hepatotoxic , dose – related peripheral neuritis ( which is ameliorated by giving pyridoxine), G.I. upset , and rash. 2) Rifampin( Rif) : 10 – 20 mg/kg/day Po single dose, is bactericidal by decreasing RNA synthesis. S.E.: G.I. upset , pruritus, hepatitis, TCP, and it can turn body secretions orange color. 3) Pyrazinamide ( PZA ) : 30- 40 mg/kg/day Po single dose, is bactericidal in acidic media e.g. M.TB within the macrophages or inflammatory lesions. It is used with other agents for initial treatment . S.E. : G.I. upset , hepatotoxic , hyperuricemia. 4) Ethambutol ( ETB ) : is bactericidal at doses > 25 mg/kg/ by inhibiting RNA synthesis . It is used with other agents as 20 mg/kg/ day Po single dose. S.E. : Optic neuritis, GI upset, hypersensitivity. Less Commonly Used Agents : 1) Aminoglycosides : e.g. streptomycin ( 20-40 mg/kg/day) single i.m. , or new generations e.g. amikacin , kanamycin, capreomycin (all as 15 – 30 mg/kg/day single i.m. ). They inhibit protein synthesis , and only used in resistant cases. S.E.: ototoxic and nephrotoxic. 2) Cycloserine : is bacteriostatic , 10-20mg/kg/day in 2 divided doses. S.E. : neurotoxic ( fit , psychosis ), rash. 3) Ethionamide : 15-20 mg/kg/ day Po in two-divided doses is isonicotinic a. derivative which has good CNS- penetration. S.E. : G.I. upset , neurologic disturbances. 4) Para-amino Salicylic acid ( PAS ) : is bacteriostatic which acts by competitive inhibition of folic acid synthesis. Treatment Recommendations for non-resistant TB : 1) Latent TB Infection : INH daily for 9 mo. 2) Pulmonary or extrapulmonary TB without meningitis : INH , Rif, and PZA & ETB daily for 2 mo., followed by INH and Rif for 4 mo. 3) TB meningitis : INH , Rif, PZA , and an aminoglycoside or ethionamide daily for 2mo. , followed by INH and Rif for 7 – 10 mo. Drug – Resistant TB : can occur in 20 – 50 % of cases , it is usually " Primary " i.e. M.TB is already resistant to a particular drug , rather than " secondary " i.e. it emerge during therapy due to poor adherence with therapy by the patient or inadequate treatment . This condition requires prolonged therapy with at least 2 bactericidal agents to which the infecting strain is susceptible. Indications of Corticosteroid Therapy in TB : 1) Miliary TB (oral prednisolone 1 – 2 mg/kg/day in 1 – 2 doses for 4 – 6 wk.). 2) TB meningitis ( to decrease vasculitis, inflammation , and I.C.P. ) 3) Endobronchial TB . 4) TB Pericardial effusion ( in < 4 % of cases ) to relieve symptoms and constriction. 5) Some severe cases of TB pleural effusion. Prevention: 1) Case finding and treatment : will interrupt transmission of infection , so any patient with symptoms suggestive of TB, or in close contact with an infectious adult should have T.S.T. Up to 50 % will be positive, and 1 % of contacts already have overt disease. 2) Bacille Calmette – Guérin ( BCG) Vaccination: is the only available vaccine against TB, given as a single intradermal injection , repeat vaccination is given to children who have no typical scar or no skin test reactivity following the first dose(which usually develops within 1 – 3 mo.) Local ulceration and suppurative regional adenitis occurs in < 1 % and usually resolve spontaneously, while systemic S.E. are very rare. Its effect is mainly to prevent life-threatening forms of TB in infants and young children which is time limited effect i.e. it has little effect on the ultimate incidence of TB in adults. 3) Prevention of Perinatal TB : ( which usually presents like bacterial sepsis and other congenital infections, with very high mortality rate ) mainly by appropriate testing and treatment of the mother and other family members…..

Answer 55

Febrile seizure It occurs between the age of 6 and 60 mo with a temperature of 38°C (100.4°F) or higher, that are not the result of central nervous system infection or any metabolic imbalance, and no history of prior afebrile seizures. -A simple febrile seizure is a primary generalized, usually tonic–clonic, attack associated with fever, lasting for a maximum of 15 min, and not recurrent within a 24-hr period. -A complex febrile seizure is more prolonged (>15 min), and or focal, and/or reoccurs within 24 hr. -Febrile status epilepticus is a febrile seizure lasting longer than 30 min. -Some use the term simple febrile seizure plus for those with recurrent febrile seizures within 24 hr. -Simple febrile seizures do not have an increased risk of mortality. -Complex febrile seizures may have an approximately 2-fold long-term increase in mortality, as compared to the general population, over the subsequent 2 yr., probably secondary to coexisting pathology. -There are no long-term adverse effects of having 1 or more simple febrile seizures. Although approximately 15% of children with epilepsy have had febrile seizures, only 2-7% of children who experience febrile seizures proceed to develop epilepsy later in life. Risk factors for recurrence of febrile seizures Major: (Age <1 year, Duration of fever <24 hr, and Fever 38-39C) Minor: (Family history of febrile seizures, Family history of epilepsy, Complex febrile seizure, Day care, Male gender, and Lower serum sodium at time of presentation). GENETIC FACTORS The genetic contribution to the incidence of febrile seizures is manifested by a positive family history for febrile seizures in many patients. In some families, the disorder is inherited as an autosomal dominant trait. However, in most cases the disorder appears to be polygenic. EVALUATION: Each child who presents with a febrile seizure requires a detailed history and a thorough general and neurologic examination. Investigations: I. Lumbar puncture (LP): 1- Should be performed for all infants younger than 6 mo of age who present with fever and seizure, or if the child is ill appearing. 2- At any age if there are clinical signs or symptoms of concern. 3- It is an option in a child 6-12 mo of age who is deficient in Haemophilus influenzae type b and Streptococcus pneumoniae immunizations or for whom immunization status is unknown. 4- It is an option in children who have been pretreated with antibiotics. II. EEG: If an EEG is indicated, it is delayed after more than 2 wk have passed. A- It should be restricted to cases in which epilepsy is highly suspected, and, generally, it should be used to detect the type of epilepsy rather than to predict its occurrence. B- If the patient does not recover immediately from a seizure, then an EEG can help distinguish between ongoing seizure activity and a prolonged postictal period. C- It can also be helpful in patients who present with febrile status epilepticus III. Blood studies: (serum electrolytes, Ca, PO4, Mg, and CBC) are not routinely recommended with a first simple febrile seizure. IV. Blood glucose should be determined only in children with prolonged postictal obtundation or those with poor oral intake. V. CT or MRI: is indicated if the child is neurologically abnormal and in patients with febrile status epilepticus. Treatment: 1- Parent's emotional support. 2- Antiepileptic therapy is not recommended for children with one or more simple febrile seizures. 3- If the seizure lasts for >5 min, then acute treatment with diazepam, lorazepam, or midazolam is needed. 4- Rectal diazepam use by family is given at the time of recurrence of febrile seizure lasting >5 min. alternatively, buccal or intranasal midazolam may be used and is often preferred by parents. 5- Intermittent oral diazepam can be given during febrile illnesses (0.3 mg/kg every 8 hr). Intermittent oral nitrazepam, clobazam, and clonazepam (0.1 mg/kg/day) have also been used. 6- Antipyretics do not reduce the risk of having a recurrent febrile seizure, probably because the seizure often occurs as the temperature is rising or falling. 7- Iron deficiency has been shown to be associated with an increased risk of febrile seizures, and thus screening for that problem and treating it.

Answer 56

Status Epileptics Status epilepticus (SE) is a medical emergency that should be anticipated in any patient who presents with an acute seizure. The ILAE has refined the definition of SE to reflect the time at which treatment should be initiated (t1) and time at which continuous seizure activity leads to long-term sequelae (t2) such as neuronal injury, depending on the type of SE, (t1 = 5 min, t2 ≥ 30 min) in generalized seizure. in the past the definition Continuous seizure activity or recurrent seizure activity without regaining of consciousness lasting for >30 min. Impending Status epilepticus: seizures between 5 and 30 min. The most common type is convulsive status epilepticus (generalized tonic, clonic, or tonic–clonic), but other types do occur, including (complex partial, absence), myoclonic status, epilepsia partialis continua, and neonatal status epilepticus. Nonconvulsive status epilepticus: manifests as a confusional state, dementia, hyperactivity with behavioral problems, fluctuating impairment of consciousness, hallucinations, and psychotic symptoms. Refractory status epilepticus: failure to respond to therapy, usually with at least 2 medications. Etiology: • New-onset epilepsy of any type. • Drug intoxication (tricyclic antidepressants). • Drug and alcohol abuse in adolescence. • AEDs withdrawal or overdose. • Hypoglycemia, hypocalcemia, hyponatremia, hypomagnesemia. • Acute head trauma. • Encephalitis, meningitis, ischemic stroke, intracranial hemorrhage. • Pyridoxine, and folinic acid dependency. • Inborn errors of metabolism (nonketotic hyperglycinemia) in neonates. • Hypertensive encephalopathy, renal or hepatic encephalopathy. • Brain tumors, brain malformations, and neurodegenerative disorders. Mechanisms The mechanisms leading to the establishment of sustained seizure activity seen in SE appear to involve (1) failure of desensitization of AMPA glutamate receptors, thus causing the persistence of increased excitability, and (2) reduction of GABA-mediated inhibition as a result of intracellular internalization of GABAA receptors.

Answer 57

Management  Continuous attention to ABC (with continuous monitoring of vital signs including ECG).  Determination and management of the underlying etiology (e.g., hypoglycemia).  Laboratory studies including glucose, sodium, calcium, are ordered as routine practice.  Blood and spinal fluid cultures, toxic screens, and tests for inborn errors of metabolism are often needed.  AED levels need to be determined in known epileptic children already taking these drugs.  EEG is helpful in ruling out pseudo–status epilepticus (psychological conversion reaction mimicking SE) or other movement disorders (chorea, tics), rigors, clonus with stimulation, and decerebrate/decorticate posturing. The EEG can also be helpful in identifying the type of SE (generalized vs focal), which can guide further testing for the underlying etiology and further therapy. EEG can also help distinguish between postictal depression and later stages of SE in which the clinical manifestations are subtle (e.g., minimal myoclonic jerks) or absent (electroclinical dissociation), and can help in monitoring the therapy, particularly in patients who are paralyzed and intubated. Neuroimaging must be considered after the child has been stabilized, especially if it is indicated by the clinical manifestations, by an asymmetric or focal nature of the EEG abnormalities, or by lack of knowledge of the underlying etiology. Physical and neurological examination: for any evidence of trauma, papillodema., bulging anterior fontanel, lateralizing neurological signs suggesting ↑ I.C.P., manifestation of sepsis or meningitis, retinal hemorrhage, acidotic breathing and dehydration. evidence of metabolic diseases, constriction or dilatation of pupils. Drugs: should be given by intra venous route. Phenytoin must not be given in glucose solution, because it is precipitated in it. Diazepam: given directly in the vein (0.1-0.3 mg/kg) with maximum dose of 10 mg at a rate not more than (2 mg / min), 2 doses 5 min apart. It can be used rectally (0.3-0.5 mg/kg) diluted in 3ml 0.9% NaCl. The drug has short half-life and may cause hypotension and respiratory depression especially if given with barbiturate. Its therapeutic serum level occurs within 5-10 min. Lorazepam: is equally effective with long half- life and less respiratory depression. Its sublingual, I.V and rectal dose (0.05 -0.1 mg/kg). If intravenous access is not available, buccal midazolam or intranasal lorazepam can be used. In infants, a trial of pyridoxine is often warranted. If the emergent therapy with a benzodiazepine is unsuccessful (persistent seizures 5 min after the second benzodiazepine dose), fosphenytoin, valproate, or levetiracetam is the recommended option for urgent therapy. Fosphenytoin: The loading dose is usually 15-20 PE/kg. The maintenance dose can be started right away or, more commonly, in 6 hr. The rate of infusion of fosphenytoin and phenytoin must be not more than 0.5-1 mg/kg/min. The subsequent medication is often phenobarbital, the loading dose in neonates is usually 20 mg/kg, but in infants and children the dose is 5-10 mg/kg. The dose is repeated if there is no adequate response. Intravenous valproate is given at a loading dose of 20-40 mg/kg, but its use should be avoided in patients younger than 2 yr of age and in those with hepatic dysfunction or mitochondrial disease.  After the second or third medication is given, and sometimes before that, the patient might need to be intubated.  All patients with, even the ones who respond, need to be admitted to the ICU for completion of therapy and monitoring.  For refractory cases, an intravenous bolus of midazolam, propofol, pentobarbital, or thiopental is usually initially used.  Super refractory cases: continuous infusion of above drugs. For non-convulsive status epilepticus: trials of oral or sometimes parenteral AEDs without resorting to barbiturate coma or overmedication that could result in respiratory compromise. Prolonged non-convulsive complex partial status epilepticus can last for as much as 4-12 weeks, with patients manifesting psychotic symptoms and confusional states. These cases can be resistant to therapy. Some of these cases appear to improve with the use of steroids or IVIG. Potential therapies under study for convulsive status epilepticus include induction of acidosis (e.g., by hypercapnia), and ketogenic diet and treatment by hypothermia.

Answer 58

Conditions that mimic seizures These conditions share features with epilepsy and may be associated with altered level of consciousness, tonic or clonic movement or cyanosis. Benign paroxysmal vertigo: Typically develops in toddlers. It remits by 5 years of age. The attack develops suddenly associated with ataxia causing the child to fall or refuse to walk or sit. Horizontal nystagmus may occur during the attack. The child appears frightened and pale, nausea and vomiting may be prominent, consciousness and verbalization aren’t disturbed. The attack last (secs – mins) and the frequency vary from daily to monthly; vertigo is verbalized by older child. Those children are susceptible to motion sickness and migraine, negative neurological exam. MRI and EEG are normal, but caloric testing, can show abnormal vestibular function. Treatment: Diphenhydramine (5 mg / Kg / 24 h) → max 300 mg /day (orally, I.M., I. V., rectally) Night terrors: are common especially in boys between (5-7) y. they occur in (1- 3%) of children and usually short – lived, it starts suddenly usually between midnight and 2:00 A.M when the child screams and appears frightened with dilated pupils, tachycardia and hyper ventilation, there is little or no verbalization and is unaware of surrounding, sleep follows in few min and there is total amnesia the following morning. 1/3 of them experience somnambulism. Treatment: Short course of diazepam may be considered for protracted cases. Breath – Holding spells: there are 2 major types: Cyanotic spells: It is the more common type. Upsetting or scolding an infant provokes it. The attack preceded by brief shrill cry followed by forced expiration and apnea and rapid onset of generalized cyanosis and loss of consciousness which may be associated with repeated generalized clonic jerks, opisthotonus and bradycardia. Interictal EEG is normal. It is rare before 6m of age peaked at 2y and abate by 5y of age. Treatment: Support and reassurance of the parents. Placing the child safely in bed and refusing to cuddle, play or hold the child when recovery is complete because that will reinforce the child behavior. Pallid spells: It is typically initiated by a painful experience or sudden startle, the child stop breathing, rapidly loss consciousness, becomes pale and hypo tonic and may have tonic seizure, normal inter ictal EEG. The attack can be induced spontaneously by ocular compression that produce oculo cardiac reflex, but don’t attempt to do that. Vagal syncope: Vasovagal (neurocardiogenic) is usually triggered by dehydration, heat, standing for a long time without movement. There is initially pallor and sweating followed by blurring of vision, dizziness, nausea, and then gradual collapse with loss of consciousness. Urinary incontinence in 10% and a brief period of convulsive jerks occur in 50%. Postictal confusion can also occur. Abdominal pain, a common aura in temporal lobe epilepsy, occurs in vasovagal syncope. Most children with vasovagal syncope have an affected first-degree relative. EEG is normal and the tilt test has been used for diagnostic purposes. Management:  Avoidance of precipitating factors (maintenance of hydration, avoidance of standing still, rising slowly from sitting, first aid measures, raise legs, positioning).  Treatment of any accompanying or underlying medical conditions (anemia, adrenal insufficiency, cardiac, etc.).  β-blockers or flurohydrocortisone therapy may be needed. Pseudo seizures: - Typically occur between (10 -18) y of age, more frequent in females. It occurs in many patients with past history of epilepsy. No cyanosis, normal reaction of pupils to light, no loss of sphincter control, no tongue biting. The patients are likely to have neurotic personality, no effect for anticonvulsant. EEG shows excess muscle artifact but normal back ground.

Answer 59

Cerebral palsy Non progressive disturbances in the developing fetal or infant brain. Cerebral palsy is a disorder of motor function with or without abnormal posture The clinical manifestations of the disorder may change over time, but the causative lesion is static The incidence is 3.6/1000 with a male/female ratio of1.4/1. The prevalence of CP has increased due to the enhanced survival of very premature infants weighing <1,000 g, who go on to develop CP at a rate of .approximately 15/100 - :Etiology Most common cause of cp is prematurity and low birth weight not hypoxia 1.Prenatal: - Congenital infections like (CMV, toxoplasmosis and rubella), cerebral agenesis, intra uterine bleeding, radiation, toxins, anoxia, genetic and metabolic disorders. 2.Perinatal :-( cerebral anoxia, intra ventricular hemorrhage, birth trauma) 3.Postnatal :-( meningitis, encephalitis, hyper bilirubinemia, hypo glycaemia,hyper natremia, subdural hematoma and toxins) Types according to physiological classification ❖ Spastic: 70% • hemiplegia- diplegiaquadriplegia- Dyskinetic • chorathetiod- dystonic- Hypotonic • Mixed • : FUNCTIONAL classification ❖ .Class I → no limitation of activity • .Class II → slight – moderate limitation • .Class III → moderate – severe limitation • .Class IV → no useful physical activity • whereas the topographic taxonomy indicates the involved .extremities

Answer 60

Spastic hemiplegia (25%) Cause: Stroke: in utero or neonatal due to Thrombophilic disorders, Infection, Genetic/developmental, Periventricular hemorrhagic infarction C.F.: Decreased spontaneous movement on the effected side and show hand preference at a very early age. - Circumduction gait, dystonia on running, growth arrest of affected side. Equina varus, walking on tip to, ankle clonus, increases DTR. -About one third of patients have a seizure disorder that usually develops in first year or 2nd. .-25% have cognitive abnormalities Dx. A CT scan or MRI study may show an atrophic cerebral hemisphere with a .dilated lateral ventricle contra lateral to the side of affected extremities Spastic diplegia (35%): - bilateral spasticity of the legs Cause: is strongly associated with damage to the immature white matter .(prematurity) .C.F In sever spasticity difficult application of diaper because of excessiveadduction of the hips. - Scissoring posture of lower extremities during vertical .suspension Commando crawls. -Seizure in minority of cases, the prognosis for normal intellectual .development is good The most common neuropathological finding in children with spastic Diplegia is PVL (periventricular leukomalacia), Periventricular cysts or scars in white matter, enlargement of ventricles, which is visualized on MRI in more than .70% of cases Spastic quadriplegia (20%): -cause hypoxic ischemic encephalopathy Is the most severe form of CP because of marked motor impairment of all extremities and the high association with intellectual disability and \seizures. Swallowing difficulties are common as a result of supranuclear bulbar palsies. The most common lesions seen on pathologic examination or on MRI scanning are .severe PVL and Multicystic cortical encephalomalacia

Answer 61

Athetoid (choreoathetoid, extrapyramidal, or dyskinetic) (15%) Affected infants are characteristically hypotonic with poor head control and marked head lag and develop variably increased tone with rigidity and dystonia .over several years Unlike spastic diplegia, the upper extremities are generally more affected than .the lower extremities in extrapyramidal CP Feeding may be difficult, and tongue thrust and drooling may be prominent. Speech is typically affected because the oropharyngeal muscles are involved. .Speech may be absent or sentences are slurred Generally, upper motor neuron signs are not present, seizures are uncommon, .and intellect is preserved in many patients .dyskinetic CP is the type most likely to be associated with birth asphyxia Athetoid CP can also be caused by kernicterus secondary to high levels of bilirubin, and in this case the MRI scan shows lesions in the globuspallidus .bilaterally Extrapyramidal CP can also be associated with lesions in the basal ganglia and thalamus caused by metabolic genetic disorders such as mitochondrial .disorders and glutaric aciduria

Answer 62

Ataxias Ataxia is the inability to make coordinated movements, usually due to a disorder of the cerebellum and/ or sensory pathways in the posterior columns of the spinal cord. Ataxias may be generalized or primarily affect gait or the .hands and arms. They may be acute or chronic Causes of acute or recurrent ataxia 1.Brain tumors 2 .Drugs: piperazine, phenytoin, alcohol 3.Encephalitis (brain stem) 4.Migraine: Basilar and Benign paroxysmal vertigo 5.Post infectious/ immune :- a- Acute cerebellar ataxia (ACA): occurs primarily in children between 1-3 years of age and is a diagnosis by exclusion. It often follows a viral infection like (varicella, coxsackie virus, or echo virus) infection by 2-3 weeks. b- Cerebellar abscess.c- Acute labyrinthitis. 6 .Trauma 7 .Vascular disorders: Cerebellar hemorrhage, and Kawasaki disease 8 .Pseudo ataxia (Epileptic) 9.Genetic disorders: (Maple syrup disease, and Pyruvate dehydrogenase deficiency) Causes of Chronic or Progressive Ataxia 1.Brain tumors: Cerebellar tumors, Medulloblastoma, Ependymoma, Supra tentorial tumors, Neuroblasoma 2.Congenital malformation: Dandy-Walker malformation, Chiare malformation 3.Hereditary ataxia: Abetalipoproteinemia, Ataxia- telangectasia, Friedreich ataxia

Answer 63

:Diagnosis of CP .History (also review pregnancy and delivery records).Physical exam (including thorough neurologic exam).EEG, CT scan, MRI.Tests for hearing and visual functionsGenetic evaluation in patients with congenital malformations or evidence of.metabolic disorder Management Multidisciplinary approach 1.Pediatrician: co-ordinating role 2.Physiotherapist.is involve with the child from an early stage, help in preventing severe contractures and deformity 3.Occupational therapist. Is involved in adapting the environment to aid the child functioning. Use of adaptive equipment (motorized wheel .chair, special feeding device) 4.Communication therapist: is involved early, providing help with feeding problem and later with speech 5.Surgery: for CDH. (Adductor tenotomy and psoas transfer and release), rhizotomy procedure (division roots of spinal nerve) which used in severe spastic diplegia, tenotomy for Achilles’ tendon. 6.Care for lower urinary tract dysfunctions . 7.Drugs :- a. Treatment of severe spasticity by: oral diazepam, oral baclofen, dantrolene, intrathecal baclofen, and botulinum toxin injected into .specific muscle groups b. Botulinum toxin could be injected into salivary glands to reduce the .severity of drooling that is seen in 10-30% of patients with CP c. reserpine or tetrabenazine can be useful for hyperkinetic movement .disorders including athetosis or chorea d. treatment of dystonia by small doses of levodopa. Artane and Carbamazepine is sometimes useful . e. Treatment of seizures by anticonvulsant . 8.Hearing aids . 9.Special education. - :Prevention 1.Good pre natal care 2.Prevention of kernicterus 3.Care for LBW infants 4.Treatment of apneic episodes 5.Prenatal treatment of the mothers in premature labour with magnesium sulphate. 6.several large trials have shown that cooling term infants with hypoxic ischemic encephalopathy to 33.3°C for 3 days, starting within 6 hr of birth, reduces the risk of the dyskinetic or spastic quadriplegia form of . CP Prognosis: - depend on .Severity of the condition (1 .Associated intellectual defect (2 .Adequate education and available facilities (3 .Centers that treat these conditions (4 .Type of C.P (5

Answer 64

It’s the most common cause of fever associated with signs and .symptoms of CNS disease in children In general, viral infections of the CNS are much more common than bacterial infections, which, in turn, are more common than fungal and parasitic infections; regardless of etiology, most patients with CNS .infection have similar clinical manifestations Infection of the CNS may be diffuse or focal. Meningitis and encephalitis are examples of diffuse infection. Meningitis implies primary involvement of the meninges, whereas encephalitis indicates brain parenchymal involvement. Because these anatomic boundaries are often not distinct, many patients have evidence of both meningeal and parenchymal involvement and should be considered to have meningoencephalitis. Brain abscess is the best example of a focal . infection of the CNS Acute Bacterial Meningitis beyond the Neonatal Period Bacterial meningitis is one of the most potentially serious infections .occurring in infants and older children The most common causes of bacterial meningitis in children older than 1 mo. of age in the United States are Streptococcus pneumoniae and Neisseria meningitidis. Bacterial meningitis caused by S. pneumonia and Haemophilus influenzae type b has become much less common in developed countries since the introduction of universal immunization .against these pathogens beginning at 2 mo of age A major risk factor for meningitis is the lack of immunity to specific pathogens associated with young age. Additional risks include recent colonization with pathogenic bacteria, close contact (household, daycare centers, college dormitories, military barracks) with individuals having invasive disease caused by N. meningitidis or H. influenza type b, crowding, poverty, black or Native American race, and male gender. The mode of transmission is probably person-to-person contact through .respiratory tract secretions or droplets Defects of the complement system (C5-C8) are associated with recurrent meningococcal infection, and defects of the properdin system are associated with a significant risk of lethal meningococcal disease. Splenic dysfunction (e.g., in sickle cell anemia) or asplenia (caused by trauma or a congenital defect) is associated with an increased risk of pneumococcal, H. influenzae type b, and meningococcal sepsis and meningitis. Tlymphocyte defects (congenital or acquired) are associated with an .increased risk of Listeria monocytogenes infections of the CNS A congenital or acquired CSF leak across a mucocutaneous barrier, such as a lumbar dural sinus, or CSF leakage through a rupture of the meninges as a result of a basal skull fracture, is associated with an increased risk of pneumococcal meningitis. CSF shunt infections increase the risk of meningitis caused by Pseudomonas aeruginosa,Staphylococcus spp

Answer 65

PATHOLOGY AND PATHOPHYSIOLOGY A meningeal purulent exudate of varying thickness may be distributed around the cerebral veins, venous sinuses, convexity of the brain, and cerebellum, and spinal cord. Ventriculitis with bacteria and inflammatory cells in ventricular fluid may be present (more often in neonates), as may subdural effusions and, rarely, empyema. Cerebral infarction, resulting from vascular occlusion because of inflammation, vasospasm, and thrombosis, is a frequent sequela. Inflammation of spinal nerves and roots produces meningeal signs, and inflammation of the cranial nerves produces cranial neuropathies of optic, oculomotor, facial, and auditory nerves. Increased ICP is a result of cell death (cytotoxic cerebral edema), cytokine-induced increased capillary vascular permeability (vasogenic cerebral edema), and, possibly, increased hydrostatic pressure (interstitial cerebral edema) after obstructed reabsorption of CSF in the arachnoid villus or obstruction of the flow of fluid from the ventricles. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may produce excessive water retention and potentially increase the risk of .elevated ICP Hydrocephalus can occur as an acute complication of bacterial meningitis. It most often takes the form of a communicating hydrocephalus caused by adhesive thickening of the arachnoid villi around the cisterns at the base of the brain. Raised CSF protein levels are partly a result of increased vascular permeability of the blood–brain barrier and the loss of albumin-rich fluid from the capillaries and veins traversing the subdural space. Continued transudation may result in subdural effusions, usually found in the later phase of acute bacterial meningitis. Hypoglycorrhachia (reduced CSF glucose levels) is .attributable to decreased glucose transport by the cerebral tissue

Answer 66

Clinical features The signs and symptoms of meningitis are related to the nonspecific findings associated with a systemic infection and to manifestations of meningeal irritation. Nonspecific findings include fever, anorexia and poor feeding, headache, symptoms of upper respiratory tract infection, myalgias, arthralgias, tachycardia, hypotension, and various cutaneous .signs, such as petechiae, or an erythematous macular rash Meningeal irritation is manifested as nuchal rigidity, back pain, Kernig sign (flexion of the hip 90 degrees with subsequent pain with extension of the leg), and Brudzinski sign (involuntary flexion of the knees and .hips after passive flexion of the neck while supine) In children, particularly in those younger than 12-18 mo, Kernig and Brudzinski signs are not consistently present. Increased ICP is suggested by headache, emesis, bulging fontanel or diastasis (widening) of the sutures, oculomotor (anisocoria, ptosis) or abducens nerve paralysis, hypertension with bradycardia, apnea or hyperventilation, decorticate or decerebrate posturing, stupor, coma, or signs of herniation. Papilledema is uncommon in uncomplicated meningitis and should suggest a more chronic process, such as the presence of an intracranial abscess, subdural empyema, or occlusion of a dural venous sinus. Focal neurologic signs .usually are a result of vascular occlusion Cranial neuropathies of the ocular, oculomotor, abducens, facial, and auditory nerves may also be the result of focal inflammation. Overall, approximately 10-20% of children with bacterial meningitis have focal .neurologic signs Seizures (focal or generalized) caused by cerebritis, infarction, or electrolyte disturbances occur in 20-30% of patients with meningitis. Seizures that occur on presentation or within the 1st 4 days of onset are usually of no prognostic significance. Seizures that persist after the 4th day of illness and those that are difficult to treat may be associated with a .poor prognosis Alterations of mental status are common among patients with meningitis and may be the consequence of increased ICP, cerebritis, or hypotension; manifestations include irritability, lethargy, stupor, .obtundation, and coma. Comatose patients have a poor prognosis .Additional manifestations of meningitis include photophobia

Answer 67

Diagnosis The diagnosis of acute pyogenic meningitis is confirmed by analysis of the CSF, which typically reveals microorganisms on Gram stain and culture, a neutrophilic pleocytosis, elevated protein, and reduced glucose concentrations. LP should be performed when bacterial meningitis is suspected. Contraindications for an immediate LP include (1) evidence of increased ICP (other than a bulging fontanel), such as 3rd or 6th cranial nerve palsy with a depressed level of consciousness, or hypertension and bradycardia with respiratory abnormalities (2) severe cardiopulmonary compromise requiring prompt resuscitative measures for shock or in patients in whom positioning for the LP would further compromise cardiopulmonary function; and (3) infection of the skin overlying the site .of the LP. Thrombocytopenia is a relative contraindication for LP LP may be performed after increased ICP has been treated or a brain abscess has been excluded. Normal healthy neonates may have as many as 30 leukocytes/mm3 (usually <10), but older children without viral or bacterial meningitis have <5 leukocytes/mm3 in the CSF; in both age groups there is a predominance of lymphocytes or monocytes. Pleocytosis with a lymphocyte predominance may be present during the early stage of acute bacterial meningitis; conversely, neutrophilic pleocytosis may be present in patients in the early stages of acute viral meningitis. The Gram stain is positive in 70-90% of patients with untreated bacterial meningitis. CSF obtained from children with bacterial meningitis can be negative on Gram stain and culture as early as 2-4 hr after administration of antibiotics, especially in situations of N. meningitidis and sensitive S. pneumoniae meningitis. However, pleocytosis with a predominance of neutrophils, an elevated protein level, and a reduced concentration of CSF glucose will usually persist for .several days after the administration of appropriate parenteral antibiotics Latex agglutination: Helpful in partially treated meningitis Specific but not that sensitive. PCRs are available for neisseria and pneumococcus,Both are sensitive .and specific A traumatic LP may also complicate the interpretation of CSF tests, as CSF leukocytes and protein concentration are significantly affected by traumatic LPs. Typically, the Gram stain, culture, and glucose level are unlikely to be influenced by blood in a CSF sample. Blood cultures should be performed in all patients with suspected meningitis. Blood cultures reveal the responsible bacteria in up to 80-90% of cases of meningitis. Peripheral WBC, CSF lactate, procalcitonin, and various cytokines are used to differentiate .bacterial (usually elevated) from viral causes of meningitis

Answer 68

TREATMENT The therapeutic approach to patients with presumed bacterial meningitis .depends on the nature of the initial manifestations of the illness A child with 1) rapidly progressing disease of less than 24 hr duration, or 2) have a more protracted subacute course and become ill over a 4–7-day period; in the absence of increased ICP, should receive antibiotics as soon as possible after an LP is performed. If there are signs of increased ICP or focal neurologic findings, antibiotics should be given without performing an LP and before obtaining a CT scan. Increased ICP should be treated .simultaneously Initial Antibiotic Therapy The initial (empirical) choice of therapy for meningitis in immunocompetent infants and children is primarily influenced by the antibiotic susceptibilities of S. pneumonia . In the United States, 25-50% ;of strains of S. pneumoniae are currently resistant to penicillin vancomycin (60 mg/kg/24 hr), given every 6 hr plus cefotaxime (300 mg/kg/24 hr, given every 6 hr) or ceftriaxone (100 mg/kg/24 hr administered once per day or 50 mg/kg/dose, given every 12 hr) for 10-14 .days Most strains of N. meningitidis are sensitive to penicillin and .cephalosporins for 5-7 days For H. influenzae type b, approximately 30-40% of isolates of H. influenzae type b produce β-lactamases and, therefore, are resistant to ampicillin. These β-lactamase–producing strains are sensitive to the .extended-spectrum cephalosporins cefotaxime (300 mg/kg/24 hr, given every 6 hr) or ceftriaxone (100 mg/kg/24 hr administered once per day or 50 mg/kg/dose, given every 12 .hr) for 7-10 days should also be used in initial empirical therapy If L. monocytogenes infection is suspected, as in young infants or those with a T-lymphocyte deficiency, ampicillin (300 mg/kg/24 hr, given every 6 hr) also should also be given because cephalosporins are inactive against L. monocytogenes. Intravenous trimethoprim-sulfamethoxazole is an alternative treatment for L. monocytogenes and has documented .clinical efficacy If patient immunecompromised and Gram-negative bacterial meningitis are suspected, initial therapy might include ceftazedime and an .aminoglycoside or meropenem Repeat examination of CSF is indicated in some neonates, in all patients with Gram-negative bacillary meningitis, or in infection caused by a βlactam–resistant S. pneumoniae. The CSF should be sterile within 24-48 .hr of initiation of appropriate antibiotic therapy Corticosteroids Rapid killing of bacteria in the CSF effectively sterilizes the meningeal infection but releases toxic cell products after cell lysis (cell wall endotoxin) that precipitate the cytokine-mediated inflammatory cascade may produce additional neurologic injury with worsening of CNS signs and symptoms. Among children with meningitis caused by H. influenza type b, corticosteroid recipients have a shorter duration of fever, lower CSF protein and lactate levels, and a reduction in sensorineural hearing loss

Answer 69

Supportive Care Pulse rate, blood pressure, and respiratory rate should be monitored frequently. Neurologic assessment, including pupillary reflexes, level of consciousness, motor strength, cranial nerve signs, and evaluation for seizures, should be made frequently in the 1st 72 hr, when the risk of neurologic complications is greatest. Important laboratory studies include an assessment of blood urea nitrogen; serum sodium, chloride, potassium, and bicarbonate levels; urine output and specific gravity; complete blood .and platelet counts Seizures are common during the course of bacterial meningitis. Immediate therapy for seizures includes intravenous diazepam (0.1- 0.2 mg/kg/dose), and careful attention paid to the risk of respiratory suppression. Serum glucose, calcium, and sodium levels should be monitored. After immediate management of seizures, patients should receive phenytoin (15-20 mg/ kg loading dose, 5 mg/kg/24 hr maintenance) to reduce the likelihood of recurrence. Phenytoin is preferred to phenobarbital because it produces less CNS depression and .permits assessment of a patient’s level of consciousness Fever associated with bacterial meningitis usually resolves within 5-7 days of the onset of therapy. Prolonged fever (>10 days) is noted in approximately 10% of patients. Prolonged fever is usually caused by ,intercurrent viral infection, nosocomial or secondary bacterial infection thrombophlebitis, or drug reaction. Secondary fever refers to the recrudescence of elevated temperature after an afebrile interval. Nosocomial infections are especially important to consider in the evaluation of these patients. Pericarditis or arthritis may occur in patients .being treated for meningitis, especially that caused by N. meningitidis Involvement of these sites may result either from bacterial dissemination .or from immune complex deposition Thrombocytosis, eosinophilia, and anemia may develop during therapy for meningitis. Anemia may be a result of hemolysis or bone marrow suppression. Disseminated intravascular coagulation is most often associated with the rapidly progressive pattern of presentation and is noted most commonly in patients with shock and purpura. High mortality .rate occurs in pneumococcal meningitis

Answer 70

Encephalopathy describes a diffuse brain disorder, in which two of the followings are present: 1. Altered state of consciousness, 2. Altered cognition or personality.3. Seizures. Encephalitis: encephalopathy plus CSF pleocytosis. Viral Meningoencephalitis (ME) Viral ME is an acute inflammatory process involving the meninges and, to a variable degree, brain tissue. These infections are relatively common and may be caused by a number of different agents. The CSF is characterized by pleocytosis and the absence of microorganisms on Gram stain and routine bacterial culture. In most instances, the infections are self-limited. In some cases, substantial morbidity and mortality occur. Enteroviruses are the most common cause of viral ME. Several members of the herpes family of viruses can cause ME. Herpes simplex virus (HSV) type 1 is an important cause of severe, sporadic encephalitis in children and adults. Brain involvement usually is focal; progression to coma and death occurs in 70% of cases without antiviral therapy. Varicella-zoster virus may cause CNS infection in close temporal relationship with chickenpox. Mumps is a common pathogen in regions .where mumps vaccine is not widely used Mumps ME is mild, but deafness from damage of the 8th cranial nerve .may be a sequela ME is caused occasionally by respiratory viruses (adenovirus, influenza virus, parainfluenza virus), rubeola, rubella, or rabies; it may follow live .virus vaccinations against polio, measles, mumps, or rubella The progression and severity of disease are determined by the relative degree of meningeal and parenchymal involvement, which, in part, is determined by the specific etiology. The clinical course resulting from .infection with the same pathogen varies widely The onset of illness is generally acute, although CNS signs and symptoms are often preceded by a nonspecific febrile illness of a few days’ duration. The presenting manifestations in older children are headache and hyperesthesia, and in infants, irritability and lethargy. Headache is most often frontal or generalized. Fever, nausea and vomiting, photophobia, and pain in the neck, back, and legs are common. As body temperature increases, there may be mental dullness, progressing to stupor in combination with bizarre movements and convulsions. Focal neurologic signs may be stationary, progressive, or fluctuating. Loss of bowel and bladder control may occur. Examination often reveals nuchal rigidity .without significant localizing neurologic changes, at least at the onset The diagnosis of viral encephalitis is usually made on the basis of the clinical presentation of nonspecific prodrome followed by progressive ,CNS symptoms. The diagnosis is supported by examination of the CSF which usually shows a mild mononuclear predominance. Other tests of potential value in the evaluation of patients with suspected viral ME .include an electroencephalogram (EEG) and neuroimaging studies With the exception of the use of acyclovir for HSV encephalitis, .treatment of viral meningoencephalitis is supportive

Answer 71

Acute flaccid paralysis Poliomyelitis Transmission :- Humans are the only known reservoir for the polioviruses, • which are spread by the fecal-oral route. Poliovirus has been isolated from feces for >2 wk before paralysis to several .weeks after the onset of symptoms The poliovirus primarily infects motor neuron cells in the • spinal cord (the anterior horn cells) and the medulla oblongata (the cranial nerve nuclei). Because of the overlap in muscle innervation by 2-3 adjacent segments of the spinal cord, clinical signs of weakness in the limbs develop when .more than 50% of motor neurons are destroyed Abortive Poliomyelitis • In about 5% of patients, a nonspecific influenza-like syndrome • occurs 1-2 wk after infection, which is termed abortive .poliomyelitis Nonparalytic Poliomyelitis • In about 1% of patients infected with wild-type poliovirus, signs of • abortive poliomyelitis are present, as are more intense headache, nausea, and vomiting, as well as soreness and stiffness of the .posterior muscles of the neck, trunk, and limbs

Answer 72

Paralytic Poliomyelitis Paralytic poliomyelitis develops in about 0.1% of persons infected • with poliovirus, causing 3 clinically recognizable syndromes that represent a continuum of infection differentiated only by the portions of the CNS most severely affected. These are (1) spinal paralytic poliomyelitis, (2) bulbar poliomyelitis, and (3) .polioencephalitis Once the temperature returns to normal, progression of paralytic • .manifestations stops Little recovery from paralysis is noted in the 1st days or weeks, but, • .if it is to occur, is usually evident within 6 mo The return of strength and reflexes is slow and may continue to • .improve as long as 18 mo after the acute disease Lack of improvement from paralysis within the 1st several weeks or • months after onset is usually evidence of permanent paralysis. Atrophy of the limb, failure of growth, and deformity are common .and are especially evident in the growing child Poliomyelitis should be considered in any unimmunized or • .incompletely immunized child with paralytic disease The combination of fever, headache, neck and back pain, • asymmetric flaccid paralysis without sensory loss, and CSF .pleocytosis does not regularly occur in any other illness

Answer 73

Differential Diagnosis In Guillain-Barre syndrome: which is the most difficult to • distinguish from poliomyelitis, the paralysis is characteristically symmetric, and sensory changes and pyramidal tract signs are common; these are absent in poliomyelitis. Fever, headache, and meningeal signs are less notable, and the CSF has few cells but .elevated protein content Transverse myelitis progresses rapidly over hours to days, causing • an acute symmetric paralysis of the lower limbs with concomitant anesthesia and diminished sensory perception. Autonomic signs of hypothermia in the affected limbs are common, and there is bladder dysfunction. The CSF is usually normal. Traumatic neuritis occurs from a few hours to a few days after the traumatic event, is asymmetric, acute, and affects only 1 limb. Muscle tone and deep tendon reflexes are reduced or absent in the affected limb with pain in the gluteus. The .CSF is normal There is no specific antiviral treatment for poliomyelitis. The • management is supportive and aimed at limiting progression of disease, preventing ensuing skeletal deformities, and preparing the child and family for the prolonged treatment required and for .permanent disability if this seems likely

Answer 74

Prognosis The outcome of unapparent, abortive P.M. and aseptic meningitis • syndromes is uniformly good, with death being rare and with no .long-term sequelae The outcome of paralytic disease is determined primarily by degree • and severity of CNS involvement. In severe bulbar poliomyelitis, the mortality rate may be as high as 60%, whereas in less severe bulbar involvement and/or spinal poliomyelitis, the mortality rate .varies from 5% to 10% The recovery phase lasts usually about 6 mo, beyond which • .persisting paralysis is permanent Tonsillectomy and I.M injections may enhance the risk for • .acquisition of bulbar and localized disease, respectively

Answer 75

Guillain-Barre Syndrome Guillain-Barre syndrome is a postinfectious polyneuropathy involving mainly motor but sometimes also sensory and autonomic nerves. This .syndrome affects people of all ages and is not hereditary Clinical Manifestations The onset of weakness usually follows a nonspecific gastrointestinal or respiratory infection by approximately 10 days. The original infection might have caused only gastrointestinal (especially Campylobacter jejuni, but also Helicobacter pylori), respiratory tract (especially Mycoplasma pneumoniae), or systemic (Zika virus) symptoms. Weakness usually begins in the lower extremities and progressively involves the trunk, the upper limbs, and finally the bulbar muscles, a pattern known as Landry ascending paralysis. Proximal and distal muscles are involved relatively symmetrically, but asymmetry is found in 9% of patients. The onset is gradual and progresses over days or weeks. Particularly in cases with an abrupt onset, tenderness on palpation and pain in muscles is common in the initial stages. Affected children are irritable. Weakness can progress to inability or refusal to walk and later to flaccid tetraplegia. Bulbar involvement occurs in about half of cases. Respiratory insufficiency can result. Dysphagia and facial weakness are often impending signs of respiratory failure. They interfere with eating and increase the risk of aspiration. The facial nerves may be involved. Some young patients exhibit symptoms of viral meningitis or meningoencephalitis. Extraocular muscle involvement is rare, but in an uncommon variant, oculomotor and other cranial neuropathies are severe early in the course. Miller-Fisher syndrome consists of acute external ophthalmoplegia, ataxia, and areflexia. Papilledema is found in some cases, although visual impairment is not clinically evident. Urinary incontinence or retention of urine is a complication in about 20% of cases but is usually transient. Tendon reflexes are lost, usually early in the course. The autonomic nervous system is also involved in some cases. Lability of blood pressure and cardiac rate, postural hypotension, episodes of .profound bradycardia, and occasional asystole occur Laboratory Findings and Diagnosis CSF studies are essential for diagnosis. The CSF protein is elevated to more than twice the upper limit of normal, glucose level is normal, and there is no pleocytosis. Fewer than 10 white blood cells/mm 3 are found. The results of bacterial cultures are negative, and viral cultures rarely isolate specific viruses. The dissociation between high CSF protein and a lack of cellular response in a patient with an acute or subacute polyneuropathy is diagnostic of Guillain-Barre syndrome. Motor NCVs are greatly reduced, and sensory nerve conduction time is often slow. Electromyography (EMG) shows evidence of acute denervation of muscle. Serum creatine kinase (CK) level may be mildly .elevated or normal

Answer 76

Treatment Patients in early stages of this acute disease should be admitted to the hospital for observation because the ascending paralysis can rapidly involve respiratory muscles during the next 24 hr. Respiratory effort (negative inspiratory force, spirometry) must be monitored to prevent respiratory failure and respiratory arrest. Patients with slow progression might simply be observed for stabilization and spontaneous remission without treatment. Rapidly progressive ascending paralysis is treated with intravenous immunoglobulin (IVIG), common protocols include IVIG 0.4 g/kg/day for 5 consecutive days or 1g/kg/day for 2 days. Plasmapheresis and/or immunosuppressive drugs are alternatives if IVIG is ineffective. Steroids are not effective. Combined administration of immunoglobulin and interferon is effective in some patients. Supportive care, such as respiratory support, prevention of decubiti in children with flaccid tetraplegia, and treatment of secondary bacterial infections, is .important Prognosis The clinical course is usually benign, and spontaneous recovery begins within 2-3 wk. Most patients regain full muscular strength, although some are left with residual weakness. The tendon reflexes are usually the last function to recover. Improvement usually follows a gradient opposite the direction of involvement: bulbar function recovering first, and lower extremity weakness resolving last. Bulbar and respiratory muscle involvement can lead to death if the syndrome is not recognized and treated. Although prognosis is generally good and the majority of children recover completely, 3 clinical features are predictive of poor outcome with sequelae: cranial nerve involvement, intubation, and .maximum disability at the time of presentation

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