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Literature Sources We searched for articles using both electronic and hand searching asthma jams vine purchase advair diskus 500mcg otc. We repeated the search in May 2007 asthma treatment long-term purchase advair diskus on line, adding a supplemental search targeting thrombocythemia. All searches were limited to English-language articles involving treatment of humans. Eligibility Criteria An article was included if it addressed one of the key questions. An article was excluded if it was (1) not written in English, (2) contained no original data, (3) involved animals only, (4) was solely a report of an in vitro experiment, or (5) was a case series. We excluded studies with fewer than 20 patients unless the article was primarily reporting on toxicities in sickle cell disease. We excluded trials involving other diseases if fewer than 20 patients received hydroxyurea. We allowed cohort studies of diseases other than sickle cell disease only if they described more than 100 patients treated with hydroxyurea. Although we excluded case series because they do not provide sufficient data about the effectiveness of a medication we included case reports if they had information regarding the dose of hydroxyurea and the duration of treatment that could be use to assess a causal relationship with potential toxic effects. Quality Assessment We graded the included studies on the basis of their quality with regard to reporting relevant data. We designed questions to evaluate the potential for selection bias (three items) and to assess the potential for confounding (five items). For our assessment of the quality of the qualitative studies we reviewed, we developed a nine-item form to identify key elements that should be reported when describing results from qualitative research, including a description of the population and subjects and transparency of the data collection procedures. The overall score was the percentage of the maximum possible score, ranging from 0 to 100 percent. We considered high-quality studies to be those with a Jadad score of 4 or 5, or those receiving 80 percent or more of available quality points. We then created detailed evidence tables containing information extracted from the eligible studies. We applied evidence grades to the bodies of evidence about the efficacy and/or effectiveness of hydroxyurea for the treatment of sickle cell disease in one assessment. We assessed the quality and consistency of the best available evidence, including an assessment of limitations to individual study quality (using individual quality scores), certainty regarding the directness of the observed effects in studies, precision and strength of findings, and availability (or not) of data to answer the Key Question. We classified evidence bodies pertaining to each Key Question as shown in Table 1. Results Efficacy and Effectiveness of Hydroxyurea in Children A single, small, placebo-controlled randomized trial of hydroxyurea for 6 months in Belgian children with sickle cell disease reported that the rate of hospitalization and number of days hospitalized per year were significantly lower in the hydroxyurea group (1. The mean pretreatment Hb F% ranged from 5 to 10 percent, and the on-treatment values were in the range of 15 to 20 percent. The percentage of F cells was less frequently reported, but it increased from 4 baseline in three of the four pediatric studies in which it was reported. Three of these cohort studies were retrospective; two reported increases in Hb F% comparable to those in the prospective studies. Hemoglobin concentrations increased modestly (roughly 1 gm/dL) but significantly across these studies. The frequency of pain crises was reported as an outcome in five pediatric studies, with a reduction in frequency reported in three. In one retrospective cohort study in a resource-poor environment, the frequency of pain crises declined from a median of 3 per year to a median of 0. Of note is the fact that these results were obtained using a fixed dose of hydroxyurea (15 mg/kg/day). In the retrospective study described above, the hospitalization rates decreased to 0. One study assessed the impact of hydroxyurea on secondary stroke prevention by enrolling 35 children who needed to discontinue their chronic transfusion protocol. The average hydroxyurea dose was 27 mg/kg/day, and the children were treated for a mean of 42 months. In the Belgian Registry, during 426 patient-years of hydroxyurea treatment, the rate of central nervous system events (stroke or transient ischemic attacks) was 1.

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Maintenance of an adequate airway may be achieved using oral or nasopharyngeal airways and proper head position asthma treatment in hyderabad buy cheap advair diskus 250mcg online. Careful assessment and immobilization for concomitant cervical spine injury should be undertaken asthma prophylaxis definition generic advair diskus 500 mcg. It is recommended that these interventions occur in a stepwise fashion, from less aggressive to an increasing intensity of therapy. As already mentioned, a small subset will develop chronic postconcussion syndrome. In these cases, further evaluation should be undertaken to identify and treat comorbid conditions. Chronic headaches are often best addressed by preventive pharmacotherapies such as tricyclics (amitriptyline, nortriptyline), anticonvulsants (gabapentin, topiramate), antiinflammatories, and herbal treatments (Butterbur). Maintaining a simple headache diary may allow more effective titration of medications. Cervicogenic headaches and occipital neuralgia may respond to physical therapy, neck stretching and strengthening, antiinflammatories, or local injections. Care should be taken in any patient with chronic headaches to avoid medication overuse or rebound headache. Anxiety and mood disturbances are frequent in patients suffering chronic problems. Once the underlying diagnosis has been made, proper longterm treatment may be initiated. Posttraumatic epilepsy is most frequently localization-related, and thus treatment may be targeted to either focal epilepsy medications (carbamazepine, oxcarbazepine, etc. In intractable cases, more aggressive interventions include vagal nerve stimulation or even, in selected cases, epilepsy surgery. Motor disturbances including spasticity may be addressed by antispasticity medications (baclofen, tizandine, dantrolene), bracing, and physical/occupational therapy. Cognitivebehavioral sequelae are ubiquitous after more severe injuries; often the initial step is to obtain formal neuropsychological testing to quantitate their strengths and weaknesses more objectively, followed by cognitive therapy or offlabel use of nootropic medications or stimulants. In some of the most severely injured patients, autonomic disturbances may respond to beta blockers, sedatives, gabapentin, baclofen, and bromocriptine. Patients in a persistent vegetative or minimally conscious state may benefit from amantadine, which has been shown to be effective in a randomized placebocontrolled trial. General supportive care includes maintaining adequate hydration, providing good nutrition, and proper sleep hygiene. Summary of evidencebased guideline update: Evaluation and management of concussion in sports. Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children and Adolescents. After acute hospitalization less than 30% of patients showed improvements in functional independence. Better functional recovery was observed in patients with lower neurological levels of the lesion. The main causes of injuries in developed countries are road traffic and sporting accidents, whereas falling from a height is the most common cause in developing regions. Injuries due to intentional violence are a relatively common cause of cord injury in particular areas, including parts of South America and Africa. Intra and extramedullary circulatory impairment occurs not only at the initial impact level, but also in the adjacent levels. The presence of constitutional or spondylotic narrowing of the spinal canal seems to predispose to lesions of the cord. In 50% of cases the cervical spine is affected, followed by the thoracic and lumbosacral spine, respectively.

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Postganglionic (thirdorder neuron) lesions are often benign asthma exacerbation definition order advair diskus 250mcg with visa, especially an isolated case asthma symptoms from acid reflux advair diskus 250mcg otc. Bilateral small pupils Clinical approach to pupillary abnormalities Examination of the pupil should include size, function, and shape. Small pupil An "occluded" pupil is a condition when synechia from the iris occlude the pupil. The pupil is very small and filled in with synechiae that attach from the iris to the lens. Because of severe synechia, pupils do not react either to light or to near objects. In early uveitis, a patient may have intense photophobia, ciliary injection, decreased vision, and ocular pain. The small pupil is helpful in distinguishing uveitis from acute glaucoma, which has similar symptoms except for the presence of a semidilated fixed pupil. About twothirds of diabetic patients have smaller pupils than the average for their age; however, a pupil size of 3 mm or less is uncommon. Onethird of diabetic patients have sluggish pupils, which is otherwise rare in patients under 40 years old. Pilocarpine or phospholine iodide, now rarely prescribed antiglaucoma drugs, usually cause very small pupils (about 2 mm or less) with very poor light or near reaction. With prolonged use of a computer, accommodative reflexes are sustained, and patients may have temporary myopia, small pupils, and dull eye pain. When patients then change their sight from computer to distance, their vision becomes blurred. Other causes of bilateral small pupils are hypothalamic lesions, pontine lesions, metabolic encephalopathies, and opiate use. Large pupil Unilateral small pupil Visible physiological anisocoria is common, from 0. In dim light, if the smaller pupil does not dilate or slowly dilates, pathological anisocoria should be suspected. Patients with large pupils may have visual symptoms such as photophobia (or glare reaction) and difficulty focusing, especially near focusing. Acute closedangle glaucoma can also cause a large pupil and middilated fixed positions are common. Patients present with marked visual loss, severe eye pain, nausea, and vomiting, and see a halo around light with very high intraocular pressure. Patients may complain about a unilateral large pupil in their photographs, photophobia (without pain), or blurred near vision. This large tonic pupil has poor reaction to light, slow redilatation, and light near dissociation. The lack of constriction in paralytic segments causes pupils to appear oval or scalloped. Tonic relaxation can also cause difficulty in distance refocusing and far objects become blurred after reading. Denervation hypersensitivity facilitates pupil constriction with the diluted solution compared to the normal pupil. In accommodative paresis, plus lenses are needed to aid in near visual tasks specifically in bilateral cases (10% of cases). Laboratory and imaging studies are directed to find systemic causes, especially in bilateral tonic pupils. Traumarelated large pupil Blunt trauma and ocular surgery can injure the iris sphincter. Ciliary nerve injuries by laser photocoagulation treatment for diabetic retinopathy, orbital trauma, and strabismus surgery have also been reported to cause dilated pupils. Then reverse the direction of the tests to confirm the site and characteristics of the pupillary defect.

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Marked cellular pleomorphism and high proliferative activity correlate with a poor clinical outcome 1827 asthma treatment guidelines purchase advair diskus 500 mcg otc,2251 asthma treatment algorithm 2014 order 250 mcg advair diskus overnight delivery. There is no difference in clinical behaviour of "de novo" myoepithelial carcinomas and of those arising in pleomorphic adenomas and benign myoepitheliomas 595,2251. A Clear cell myoepithelial carcinoma composed of solid nodules separated by thin fibrous septa. C Hyaline (plasmacytoid) myoepithelial cells with prominent mitotic activity and abundant eosinophilic cytoplasm. A Gland-like growths of myoepithelial tumour cells within plentiful myxoid or hyaline stroma. Nagao Definition Carcinoma ex pleomorphic adenoma is defined as a pleomorphic adenoma from which an epithelial malignancy is derived. Clinical features the typical history is that of a long-standing mass present much longer than 3 years with rapid growth over the previous few months; however, a significant proportion of patients present with a clinical history of less than three years 898,1533. Patients frequently complain of a painless mass; but pain, facial nerve palsy, and skin fixation may also occur. Occasionally, tumours are well circumscribed, scar-like or appear completely encapsulated 252,2624. Histopathology the proportion of benign versus malignant components can be quite variable. Occasionally, extensive sampling is necessary to find the benign component and in rare cases, a benign remnant might not be found. But if there is clinicopathologic documentation of a previously excised pleomorphic adenoma in the same site, then the malignancy can also Synonyms Carcinoma arising in a benign mixed tumour, carcinoma ex benign mixed tumour, carcinoma arising in a pleomorphic adenoma, malignant mixed tumour. The malignant component is most frequently a poorly differentiated adenocarcinoma (salivary duct type or not otherwise specified) or an undifferentiated carcinoma; however, virtually any form of carcinoma may be found 898,1338, 1491. An infiltrative, destructive growth pattern is the most reliable diagnostic criterion. Nuclear hyperchromasia and pleomorphism are frequent, although occasional tumours may demonstrate minimal atypia. The distinction between noninvasive and invasive tumours is based on destructive invasion through the capsule into peritumoral tissues. Pleomorphic adenoma and carcinoma components are seen in the left and right, respectively. Carcinoma cells replacing the inner ductal layer leaving outer benign myoepithelial layer. The earliest changes typically consist of tumour cells replacing the normal inner duct epithelial layer leaving the normal peripherally located myoepithelial layer intact. This differential has prognostic significance, and affects decisions regarding the need for lymph node dissection and adjuvant radiotherapy. Also carcinomas may rarely arise in a histologically benign "adenoma" ("monomorphic" adenoma); they appear to have a more favourable prognosis 1576. Cytogenetic evidence of amplification (homogeneously stained region and double minute) was found in 40% of these tumours. A Detail of adenocarcinoma with back-to-back glands composed of pleomorphic tumour cells with focal necrosis. Prognosis and predictive factors In general, the recommended therapy is wide local excision with contiguous lymph node dissection. If the carcinomatous component is low-grade and/or minimally invasive and if the tumour is adequately excised, then adjuvant radiation therapy may not be necessary. The metastatic rate varies with each series; up to 70% of patients develop local or distant metastasis 877,898,1491. Metastatic sites in order of frequency are lung, bone (especially spine), abdomen and central nervous system 786,2592. Concurrent analysis of the benign and malignant components of these tumours showed 8q and/or 12q in both components and additional alterations in 17p only in the carcinoma 651. In another study homozygous deletion of the p16 gene on chromosome 9p21 was found in carcinoma of one case and microsatellite instability was noted in both the adenoma and carcinoma components in two tumours 2510. One study showed that no patient with less than 8 mm invasion from the capsule died from the tumour, whereas all patients with invasion greater than 8 mm beyond the capsule ultimately died of disease 2624. In another study consisting of four patients with 5 mm of invasion beyond the tumour capsule, two died of disease and two were alive and well 1491.

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The loss of hair and skin pigment may be explained by dysfunction of the coppercontaining enzyme tyrosinase asthma treatment tagalog order advair diskus 500mcg amex, which catalyzes the production of melanin from tyrosine by oxidation asthma 411 buy advair diskus in india. Arterial defects are due to abnormalities in an extracellular copper enzyme, lysyl oxidase, which is involved in crosslinking collagens and elastin. Hypothermia may be explained by cytochrome c oxidase dysfunction, and the long bone demineralization may be due to peptidylglycine monooxygenase dysfunction (which leads to decrease of different endocrine factors. Although some children do not respond, those who do respond will have normal blood and cerebrospinal levels of copper within 6 weeks, accompanied by a regression of symptoms other than connective tissue manifestations. The mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia. The other clinical symptoms include dysmorphic features (resembling Down syndrome facial appearance, low set ears, growth retardation, and others), osteoporosis, hair pathology similar to Menkes disease, and erythrodermia, as well as liver disease (hepatomegaly with signs of intrahepatic cholestasis). Diagnosis Diagnosis is based on clinical presentation as well as copper metabolism abnormalities including decreased serum ceruloplasmin and total copper and increased serum nonceruloplasminbound copper and daily copper urinary excretion. Diagnosis Diagnosis is generally clinical, and is suspected when infants have typical neurological and hair changes, with confirmation by high placental copper levels, low serum copper and ceruloplasmin levels (after 6 weeks of age), or abnormal catecholamines. Manganese transporter deficiency Clinical features Manganese transporter deficiency disease was first described as an autosomal recessive disorder in 2012. The clinical symptoms of the disease include features of liver disease and movement disorders. In the two adulthoodonset Treatment the treatment for Menkes disease is subcutaneous administration of copper chloride and Lhistidine in an attempt to restore normal Chapter 169 Disorders resulting from transporter defects 691 cases described to date (45 and 47yearold patients), asymmetric parkinsonism with early postural instability was reported. Due to the actions of chelators on the metabolism of different metals, regular monitoring of serum zinc, copper, iron, and manganese should be performed to verify treatment safety. The proposed treatment is effective and leads to clinical improvement in most cases. The bestknown form typically presents in the teen to young adult years, with muscle pain and swelling after either fasting or sustained exercise. During exacerbation of the disease rhabdomyolysis and myoglobinuria occur, sometimes leading to kidney failure. There is increased risk of malignant hyperthermia in patients with this deficiency. Importantly, most patients affected with this presentation have no signs or symptoms of the disease between episodes. There are significant differences in the penetrance of the disease even among members of the same family. Pathophysiology Carnitine is ingested largely through dietary meats and dairy products. Carnitine Opalmitoyltransferase 2 is present on the inner membrane of mitochondria and it is involved in the transport of hydrophobic fatty acids. Muscle biopsy with carnitine O palmitoyltransferase 2 measurement confirms the diagnosis. Other methods used in diagnosis include enzymatic studies in fibroblasts and/or lymphocytes and other laboratory testing. Adults often have myoglobin, creatine kinase, and transaminase levels up to 400 times the upper limit of normal during an attack. Treatment Treatment is largely supportive, consisting of exercise restriction and dietary guidelines. A diet with carbohydrate loading can be protective; restriction of lipid intake is also recommended. A small amount of data suggests that prolonged exercise may be safe with intravenous glucose during exercise, but this is not practical. Carnitine supplementation combined with replacement of long chain with medium chain triglycerides may be beneficial.

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The rectouterine pouch (pouch of Douglas) is a common site for an ectopic abdominal pregnancy asthma treatment of discount 250mcg advair diskus fast delivery. Result from the fertilization of two different secondary oocytes by two different sperm; the resulting two zygotes form two blastocysts asthma treatment video cheap advair diskus generic, which implant separately into the endometrium of the uterus. Hence, the twins are no more genetically alike than are siblings born at different times. Dizygotic twins and 35% of monozygotic twins have two placentas, two amniotic sacs, and two chorions. The resulting zygote forms a blastocyst in which the inner cell mass (embryoblast) splits into two. In 65% of the cases, monozygotic twins have one placenta, two amniotic sacs, and one chorion. Form exactly like monozygotic twins, except that the inner cell mass (embryoblast) does not completely split. Hence, two embryos form, but they are joined by tissue bridges at various regions of the body. She noted that she and her husband were trying to have a baby and that she had her last period about 5 weeks ago. She said that after talking with her girlfriends about her symptoms she was a little afraid of what it could be, so she decided to see a physician. The embryoblast differentiates into two distinct cell layers: the dorsal epiblast and the ventral hypoblast. The epiblast and hypoblast together form a flat, ovoid-shaped disk known as the bilaminar embryonic disk. Within the epiblast, clefts develop and eventually coalesce to form the amniotic cavity. Hypoblast cells migrate and line the inner surface of the cytotrophoblast and eventually delimit a space called the definitive yolk sac. The epiblast and hypoblast fuse to form the prochordal plate, which marks the future site of the mouth. The cytotrophoblast does divide mitotically, adding to the growth of the syncytiotrophoblast. Primary chorionic villi formed by the cytotrophoblast protrude into the syncytiotrophoblast. The wall of the chorionic cavity is called the chorion and consists of three components: extraembryonic somatic mesoderm, cytotrophoblast, and syncytiotrophoblast. This is clinically significant because progesterone produced by the corpus luteum is essential for the maintenance of pregnancy until week 8. If implantation of a conceptus has occurred, the conceptus will be sloughed along with the endometrium. A hydatidiform mole (complete or partial) represents an abnormal placenta characterized by marked enlargement of chorionic villi. A complete mole (no embryo present) is distinguished from a partial mole (embryo present) by the amount of chorionic villous involvement. The hallmarks of a complete mole include gross, generalized edema of chorionic villi forming grape-like, transparent vesicles, hyperplastic proliferation of surrounding trophoblastic cells, and absence of an embryo/fetus. This is due to the rapid proliferation of trophoblastic cells combined with marked propensity to invade blood vessels. The central portion of the lesion is hemorrhagic and necrotic with only a thin rim of trophoblastic cells at the periphery. She tells you that she had a miscarriage about 2 months ago and "all of a sudden these other problems come up. Malnutrition and loss of appetite were excluded because she mentioned that she was eating a lot of food. All major organ systems begin to develop during the embryonic period, causing a craniocaudal and lateral body folding of the embryo. By the end of the embryonic period (week 8), the embryo has a distinct human appearance.

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Tumoral cells can cluster around blood vessels or neurons asthmatic bronchitis prevention generic 250mcg advair diskus with amex, creating the phenomenon of satellitosis asthma laba discount advair diskus 500 mcg fast delivery. Some oligodendroglial tumors demonstrate mini gemistocytes or gliofibrillary oligodendrocytes. In contrast, anaplastic oligodendrogliomas are dense, hypercellular lesions with a high mitotic index, nuclear pleomorphism, endothelial proliferation, and focal tumor necrosis. Epidemiology Oligodendroglial tumors typically afflict young to middleaged adults. Oligodendroglial tumors can develop at any age, but are distinctly uncommon in childhood, where they represent only 6% of gliomas. Prognosis for patients with oligodendroglial tumors is influenced by many variables, including clinical presentation, histological and molecular features of the tumor, and treatment administered (Table 137. Codeletion of 1p/19q, in addition to defining a tumor as oligodendroglial in lineage, denotes tumors with favorable prognosis and predictable response to radiotherapy and alkylator chemotherapy. Furthermore, the presence of 1p or 19q deletion alone is favorable, albeit it diminishes prognostic significance. Codeletion of 1p/19q is a primordial and persistent event in gliomagenesis, with twothirds of primary brain tumors with 1p/19q codeletion maintaining this profile after progression. Molecular features Oligodendroglial neoplasms harbor distinct and exclusive molecular genetic derangements and these biomarkers have prognostic and therapeutic significance. This unique genetic signature, a conse- the clinical presentation of a patient with an oligodendroglial neoplasm is influenced by tumor location and rapidity of growth. However, partial seizures are the most frequent mode of presentation (80% of patients present with seizures) and the morphology of the seizures reflects the function of the cerebral lobe involved. Highattenuation areas within the tumor may represent calcifications or, rarely, hemorrhagic foci. Intratumoral calcifications are more common in tumors with 1p/19q codeletion, can arise centrally or at tumor margins, and sometimes display a "ribbonlike" pattern. The overlying skull may show signs of pressure erosion, a feature that reflects the slowgrowing nature of the tumor. Cystic degeneration is common, and occasionally multiple cysts coalesce to form a larger cyst associated with a solid nodule, creating the appearance of a "honeycomb. There is local mass effect with effacement of the overlying sulci, without midline shift or hydrocephalus. However, advanced imaging is not considered standard of care and remains controversial as a modality for distinguishing lowgrade gliomas from highgrade gliomas. While it has been established that initial tumor size and extent of the surgical resection have an impact on longterm prognosis in lowgrade gliomas, the value of immediate surgery versus deferring surgery in lowgrade tumors until there is evidence of clinical or radiological progression in patients with minimal symptoms remains controversial. Early surgical intervention is indicated for patients with large tumors associated with intracranial hypertension, for tumors that have progressed radiographically, and for tumors associated with intractable seizures. The goals of surgery are to confirm pathology prior to further therapy and to alleviate seizures and symptoms related to mass effect. As with all gliomas, oligodendroglial tumors are infiltrative neoplasms and complete surgical resection is rarely feasible. Despite the results of these retrospective studies, there has never been a controlled clinical trial evaluating prospectively the role of surgery in lowgrade gliomas. These results raise questions about the nature of the biological mechanisms influencing malignant transformation following surgical resection. Radiotherapy Radiotherapy is an effective treatment for lowgrade gliomas, but its timing remains controversial. Highrisk patients require at least three of the following criteria: (1) age 40 years; (2) largest preoperative tumor diameter 6 cm; (3) tumor crossing midline; (4) tumor of astrocytoma histology; and (5) preoperative neurological deficit. Highgrade oligodendroglioma droglial neoplasms have established a role for chemotherapy in the initial management of this disease. Delayed toxicity may occur several months to years following radiation therapy and implicates cerebral necrosis, atrophy, hemorrhage, infarction, or neoplastic transformation.

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Metabolic acidosis asthma disease definition buy advair diskus 250 mcg without a prescription, hyperammonemia asthma peak flow chart order discount advair diskus online, and hypoglycemia are indicators of a deficient metabolic enzyme. Hyperbilirubinemia occurs in hemolytic disease and from inherited defects of conjugation. Extracellular bilirubin is unconjugated and binds to phospholipids on the plasma membrane of cells, forming a complex with the cell membrane. Ligandin is an intracellular substance that binds to the bilirubin complex and removes its toxicity; neurons do not contain ligandin. Therefore, acute bilirubin encephalopathy is associated pathologically with bilirubin staining of neurons, or "kernicterus. Premature infants are more susceptible to kernicterus at a lower level of total bilirubin compared to term infants. Infants who survive kernicterus have severe neurological sequelae, including movement disorders such as chorea, ballismus, dystonia, and tremor. Seizures Seizures occurring within 48 hours after birth are most likely from hypoxicischemic encephalopathy, intracranial hemorrhage, or hypoglycemia. Seizures occurring later are usually symptomatic seizures in the setting of infection, metabolic disturbance, pyridoxine deficiency, or inborn error of metabolism. Several types of seizures occur in the neonate and include tonic, clonic, myoclonic, and fragmentary. Fragmentary (or subtle) seizures may be challenging to manage since they are frequently associated with electroclinical dissociation. Neonates may have focal or generalized seizures; however, because the neonatal brain is not yet myelinated, generalized seizures consist of spread of focal activity, not the type of generalized convulsion that is seen in older age groups. Neurotoxins that can affect the fetus include environmental toxins, prescription medications, and recreational drugs. Once substances consumed by the mother cross the placental barrier, levels in the fetus can be higher than in the mother. Environmental toxins such as heavy metals disrupt neuronal cell migration and formation of synapses, which in turn disrupts neurotransmitter function. Lead, a common heavy metal in the environment, particularly impairs formation of neurocircuitry by disrupting dopamine, glutamate, and acetylcholine. Mercury, found in fish, impairs glial formation and creates a state of higher vulnerability in which the brain is more susceptible to damage from other toxins. Alcohol interferes with many systems in addition to the brain, including the cardiovascular, gastrointestinal, and musculoskeletal systems. In utero alcohol exposure kills neurons and stalls their migration, which leads to behavior problems. Cocaine and amphetamines have been shown to interfere with monoamine function and change the maturation of cells that regulate focus and emotion. Based on the metabolism and halflife of the drugs used, the time frame of presentation of withdrawal symptoms varies and can occur within 1 day to 3 weeks. Benzodiazepine and barbiturate withdrawal symptoms are similar to opiate withdrawal symptoms, but due to the longer halflife of these medications withdrawal symptoms may present as late as 2 weeks of age. Signs of withdrawal include rigidity, tremors, irritability, sneezing, yawning, and feeding problems, and these manifestations can be scored using a neonatal abstinence scoring system. These medications are administered using a stepwise weaning schedule, and, in combination with a lowstimulation environment, most neonates can be safely weaned off these medications within several weeks. However, once neonates have completed a weaning program, they often still manifest neurological abnormalities such as exaggerated startle reflex, restlessness, tremors, and developmental delays, with poor executive functioning in the schoolage years. Low birth weight and preterm births: Etiologic fraction attributable to prenatal drug exposure. Cluster of perinatal events identifying infants at high risk for death or disability. Defects in neural development and maturation arise from varied genetic, infectious, immunological, and traumatic etiologies. This chapter provides a framework for the evaluation and management of neurodevelopmental disorders, and details several conditions with a genetic basis for which clinical criteria alone can be used for diagnosis.