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P. Berek, M.A., Ph.D.

Clinical Director, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University

Deformation Deformation is an abnormal form, shape or position of a part of the body, caused by mechanical forces. Examples include intrauterine crowding as a result of twin pregnancies or uterine abnormalities, and oligohydramnios (diminished amniotic fluid) in bilateral renal agenesis leading to Potter sequence. Frequently, isolated major anomalies are associated with one or more minor anomalies. Sequence A sequence is a pattern of related anomalies that are known, or presumed, to derive from a single primary anomaly or mechanical factor. A sequence represents a cascade of events (anomalies) that are consequences of a single primary malformation, disruption or deformation. Examples include the Robin sequence (in which, because of micrognathia, there is posterior displacement of the tongue, which interferes with closure of the palatal shelves, leading to cleft palate) and clubfoot associated with spina bifida. A sequence is considered as an isolated anomaly, except when it is part of a syndrome. Multiple congenital anomaly Multiple congenital anomaly is the occurrence of two or more major anomalies that are unrelated. This means that the major anomalies are presumed to be a random association, and do not constitute a sequence or a previously recognized syndrome. Association Association is a pattern of multiple anomalies that occur with a higher than random frequency and that is not a sequence or a syndrome. As knowledge and techniques advance, some of these entities may be recognized as syndromes. Syndrome A syndrome is a pattern of multiple anomalies thought to be pathogenetically related, but not representing a sequence. They are due to a single cause ­ genetic or environmental ­ or to gene­environment interactions. Examples include Down syndrome (trisomy 21, a chromosomal abnormality), deletion of the proximal region in the long arm of chromosome 22 (a genomic disorder due to microdeletion), achondroplasia (single gene disorder), and congenital rubella syndrome (infectious cause). Despite advances in genetics, there are still clinically recognized syndromes for which the cause has not been identified. Worksheet for capacity development Surveillance Examples of potential partners Ministries of health Hospitals and, if applicable, hospital associations and clinics Regional and local health departments Primary health centres and health-care providers Community health workers/ community health volunteers Prevention X X X X X X Referral Examples of potential roles Set policies and regulations for health-care services and delivery Serve as data sources; referral sources Serve as data sources; conduits to audiences for referral and prevention activities Serve as data sources and also as sources for prevention and outreach activities Serve as potential data sources because, in many countries, these individuals are present at the delivery; provide prevention information Provide advocacy for congenital anomalies infrastructure at national and local levels; serve as dissemination channels for prevention activities and messages; potential sources for outcome data; serve as possible data sources Provide advocacy, technical assistance and expertise Provide specialized laboratory services, such as chromosome analyses, or have clinics where individuals with congenital anomalies are seen; can help drive surveillance of congenital anomalies X X X X X X X X X X Congenital anomalies associations, foundations, and other nongovernmental organizations X International organizations Medical schools/research agencies X X X 101 Appendix F Suggestions for delivering the news of a congenital anomaly diagnosis to a family Note: it is important to remember that abstractors, those individuals who will be extracting information from hospital logs or medical records for the identification and classification of congenital anomalies, do not give information to parents about a diagnosis or services. The diagnosis is communicated in person, by a health-care professional with sufficient knowledge of the condition. Health-care providers should coordinate the message to ensure consistency in the information provided to the family. Parents remember the exact words of the first contact with the health care provider even after many years. The family is informed of the diagnosis, treatment and prognosis, in their preferred language. If possible, a professional medical interpreter is present at the time of disclosure. Discuss the diagnosis, treatment and prognosis in a private, comfortable setting, free from interruptions. Information is normally given with a balanced perspective, including both positive aspects and challenges related to the congenital anomaly. Provide the information on diagnosis, treatment and prognosis in a sensitive and caring, yet confident and straightforward manner, using understandable, non-medical terms, and language that is clear and concise. In the neonatal setting, the baby is to be present, and to be referred to by name. Because there may often be guilt or blame associated with congenital anomalies, often placed on the mother, it is important to discuss these issues with the parents. Informational resources can be provided, including contact information for local and national support groups, up-to-date printed information or fact sheets, and books. The instructions for the abstraction form will help personnel participating in the congenital anomaly surveillance system to clarify doubts about how to fill in the form. Please review the variable column (third column) and the explanation column (fourth column) before completing the form. Column 1: variable number; useful when designing the database Column 2: different variable categories Column 3: variable name Column 4: instructions for completing the abstraction form for each particular variable Variable number Category Report 1 Case record identification Each case has a unique identification number. Each country can decide how to create the code, for example, the year and month the baby was born can be part of the unique identification.

Risk stratification in medulloblastoma is currently based on age, metastatic status, extent of surgical resection and histological presence or absence of diffuse anaplasia. Standard risk patients are over the age of 3 years with localized disease and without anaplastic subtype. Incorporation of molecular factors will greatly improve risk stratification for pediatric patients with medulloblastoma. Several studies are ongoing to incorporate children who are 4 or 5 years old into this strategy [20]. Increased gene or protein expression occurs more frequently even without amplification in 20­40% of medulloblastoma cases [32,33]. High-throughput technology has facilitated the rapid study of the cancer genome in cohorts of patient tumor samples. In addition, a gene expression signature was identified, consisting of only eight differentially expressed genes, which could predict patient survival more accurately than clinical risk stratification. These side-effects are most closely related to dose of radiation therapy and age at diagnosis, as well as factors at presentation such as hydrocephalus and shunting [5,6]. Patients with medulloblastoma who relapse after standard therapy have a dismal prognosis, with few long-term survivors [7,8]. The treatment strategy for standard risk medulloblastoma patients has aimed to reduce the dose of craniospinal radiation therapy. Ongoing studies for standard risk medulloblastoma patients are evaluating further radiation dose reduction with the aim of reducing radiation-associated toxicity [11­15]. Children with high-risk medulloblastoma over the age of 3 years continue to have a lower 5-year survival of 70% even with full-dose 36 Gy of craniospinal radiation therapy [10], and dose reduction to 24 Gy resulted in survival under 40% for patients with metastatic disease inappropriately treated with standard risk regimens [9]. Therefore, current strategies for high-risk patients include further therapy intensification or introduction of new agents such as isotretinoin (13-cis retinoic acid) based on preclinical studies showing apoptosis of medulloblastoma cells treated with isotretinoin [16]. Because craniospinal radiation therapy is particularly devastating to the neurocognitive development of children under the age of 3 years [5], this youngest age group is currently treated with strategies using upfront chemotherapy with the intent of delaying or avoiding radiation therapy [17­20]. Intensity of therapy, including high-dose chemotherapy with stem cell rescue, appears to 34 In addition, a strong association was observed between patient age, metastatic status and expression-based subtype. Within the last year, the results of four separate international collaborative genome-based studies of medulloblastoma have been published. The potential for further study using these now publicly available datasets is nearly unlimited. One thing is clear; the time has come to clinically view medulloblastoma as a group of molecularly distinct subtypes (summarized in Table 1) [44,45, 46,47,49,50]. In the past few decades, the ability to create genetically engineered mouse models of disease has facilitated the detailed study of a large variety of cancers as well as insight into developmental pathways [53]. In the infant population, nodular desmoplastic subtype predicts survival, and these young patients represent a group in which radiation therapy may be successfully eliminated [19,20,55,56]. This finding supports the idea that metastatic status itself may be a marker for biologic subtype rather than temporal disease progression. Mouse models that are currently being generated will greatly accelerate preclinical work in this important area. Although a number of mutations or copy number variants have been described, it remains unclear which of these drives the cancer and represents a point of vulnerability. The first unifying hypothesis suggests that deregulation of chromatin modulation is responsible for induction of these tumors [63], which is supported by the recent finding that mixed lineage leukemia gene mutations occur across medulloblastoma subtypes [48]. It remains unclear whether a chromatin remodeling event that initiates tumors represents a vulnerable driver for established tumors. Histone deacetylase inhibitors, such as vorinostat (Zolinza), broadly affect chromatin remodeling and show preclinical activity against medulloblastoma as single agents and in combination therapy [16,64] and are being evaluated in human clinical trials [65]. A commendable collaborative effort involving each of the international groups that performed these studies has resulted in a working consensus to attempt to incorporate a && && 36 This is particularly true for those patient groups in which modest improvements in outcome are possible or for efficacy equivalency studies, both of which require more patients to achieve statistically relevant endpoints. Molecular classification of all medulloblastoma using a gene expression-based approach will improve current clinical risk stratification, but will require significant coordination and centralization of testing [66,67]. Use of novel technology to measure gene expression using paraffin-embedded tissue may significantly improve feasibility in national consortium clinical trials [68]. Because driver mutations are not well understood, there are no published transgenic mouse models of this disease.

Variation in thyroid function in subclinical hypothyroidism: importance of clinical follow-up and therapy. Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Congenital hypothyroidism with a delayed thyroid-stimulating hormone elevation in very premature infants: incidence and growth and developmental outcomes. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, doubleblind, crossover study. Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. Guidance for industry: levothyroxine sodium products enforcement of August 14, 2001: compliance date and submission of new applications. Guidance on narrowing (95% rule) permissible variance in L-thyroxine tablet content. American Thyroid Association, Endocrine Society, American Association of Clinical Endocrinologists. Adverse event reporting in patients treated with levothyroxine: results of the Pharmacovigilance Task Force survey of the American Thyroid Association, American Association of Clinical Endocrinologists, and the Endocrine Society. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. Limitations of levothyroxine bioequivalence evaluation: analysis of an attempted study. Randomized, open-label, single-dose, two-way crossover study to determine the relative bioavailability of a reformulated levothyroxine tablet compared with the commercial tablet (Levoxyl) in healthy volunteers. Generic levothyroxine compared with synthroid in young children with congenital hypothyroidism. Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new Food and Drug Administration potency guidelines in healthy volunteers under fasting conditions. Comparative bioavailability of different formulations of levothyroxine and liothyronine in healthy volunteers. A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry.

Fortunately, most such cases included pathologic assessment, which is also all too infrequent in modern cases. A companion already had died, apparently the result of an attempted double suicide. The neurologic examination was normal, and an evaluation by a psychiatrist revealed a clear sensorium with ``no evidence of organic brain damage. At home he remained well for 2 days but then became quiet, speaking only when spoken to . The following day he merely shuffled about and res- Pathophysiology of Signs and Symptoms of Coma 31 Figure 1­10. Hypoxia typically causes more severe damage to large pyramidal cells in the cerebral cortex and hippocampus compared to surrounding structures. The next day (13 days after the anoxia) he became incontinent and unable to walk, swallow, or chew. He was admitted to a private psychiatric hospital with the diagnosis of depression. Deterioration continued, and 28 days after the initial anoxia he was readmitted to the hospital. His blood pressure was 170/100 mm Hg, pulse 100, respirations 24, and temperature 1018F. His extremities were flexed and rigid, his deep tendon reflexes were hyperactive, and his plantar responses extensor. Histologically, neurons in the motor cortex, hippocampus, cerebellum, and occipital lobes appeared generally well preserved, although a few sections showed minimal cytodegenerative changes and reduction of neurons. Pathologic changes were not present in blood vessels, nor was there any interstitial edema. The striking alteration was diffuse demyelination involving all lobes of the cerebral hemispheres and sparing only the arcuate fibers (the immediately subcortical portion of the cerebral white matter). The condition of delayed postanoxic cerebral demyelination observed in this patient is discussed at greater length in Chapter 5. A series of drawings illustrating levels through the brainstem at which lesions caused impairment of consciousness. For each case, the extent of the injury at each level was plotted, and the colors indicate the number of cases that involved injury to that area. The overlay illustrates the importance of damage to the dorsolateral pontine tegmentum or the paramedian midbrain in causing coma. As a result, it is no exaggeration to say that virtually any deficit due to injury of a discrete cortical area can be mimicked by injury to its thalamic relay nucleus. Hence, thalamic lesions that are sufficiently extensive can produce the same result as bilateral cortical injury. The most common cause of such lesions is the ``tip of the basilar' syndrome, in which vascular occlusion of the perforating arteries that arise from the basilar apex or the first segment of the posterior cerebral arteries can produce bilateral thalamic infarction. Other causes of primarily thalamic damage include thalamic hemorrhage, local infiltrating tumors, and rare cases of diencephalic inflammatory lesions. Examination of her brain at the time of death disclosed unexpectedly widespread thalamic neuronal loss. However, there was also extensive damage to other brain areas, including the cerebral cortex, so that the thalamic damage alone may not have caused the clinical loss of consciousness. On the other hand, thalamic injury is frequently found in patients with brain injuries who eventually enter a persistent vegetative state (Chapter 9). However, the location of the hypothalamus above the pituitary gland results in localized hypothalamic damage in cases of pituitary tumors. Patients with hypothalamic lesions often appear to be hypersomnolent rather than comatose. They may yawn, stretch, or sigh, features that are usually lacking in patients with coma due to brainstem lesions. On the other hand, we have not seen loss of consciousness with lesions confined to the medulla or the caudal pons. Twenty-five years earlier she had developed weakness and severely impaired position and vibration sense of the right arm and leg. Two years before we saw her, she developed paralysis of the right vocal cord and wasting of the right side of the tongue, followed by insidiously progressing disability with an unsteady gait and more weakness of the right limbs. Four days before coming to the hospital, she became much weaker on the right side, and 2 days later she lost the ability to swallow.

Despite chemical differences, their pharmacologic actions and antipsychotic effectiveness are similar. Haloperidol is a frequently used antipsychotic agent that is chemically different but pharmacologically similar to phenothiazines. It is potent and long acting drug, readily absorbed following oral or intramuscular administration, metabolized in liver and excreted in urine and bile. Haloperidol may cause adverse effects similar to those of other antipsychotic drugs. Usually it produces a relatively low incidence of hypotension and sedation and a high incidence of extra pyramidal effects. Routes and dosage ranges: 1-15 mg/ daily initially in divided doses, gradually increased to 100 mg /day if necessary: usual maintenance dose, 2-8 mg daily is a recommended dose for adult. Actions of neuroleptics: the antipsychotic drugs act primarily by occupying dopamine receptors in brain tissue, thereby decreasing the effects of dopamine, a catecholamine neurotransmitter. Excessive dopamine activity is believed to be an important factor in the development of schizophrenia. This concept is supported by observations of the effects of drugs that increase dopamine levels in the brain. Several weeks or months may be required for elimination of thought disorder and increased socialization. Choice of drug: the choice of particular anti-psychotic drug is largely empirical because no clear cut guidelines exist. Drugs producing greater sedation are often prescribed for agitated, over active persons and drugs producing less sedation are prescribed for those who are apathetic and withdrawn. Some clients who do not respond well to one type of antipsychotic drug may respond to another. Unfortunately, there is no way of predicting which drug is likely to be most effective for particular client. There is no therapeutic advantage, and risk of series adverse reactions is increased. If lack of therapeutic response requires that another antipsychotic drug be substituted for the one a client is currently receiving, this substitution must be done gradually. This can be avoided by gradually decreasing doses of the old drug while substituting equivalent dose of the new one. Nonphenothiazine antipsychotics are probably best used for clients with chronic schizophrenia whose symptoms have not been controlled by the phenothiazines and for clients with hyper sensitivity reactions to the phenothiazines. Clients who are unable or unwilling to take daily doses of a maintenance antipsychotic may be given periodic injections of a long- acting form of fluphenazine. Any person who has had an allergic or hypersensitivity reaction to antipsychotic drug should generally not be given that particular drug again or any drug in the same chemical group. Administer accurately Peak Rationale / explanation sedation occurs about 2 hours after administration and aids sleep. Hypotension, dry mouth and adverse reactions are less bothersome with this schedule. Observe for therapeutic effect the sedative effects of antipsychotic drugs are exerted with in 48 to 72 hours. Sedation that occurs with treatment of acute psychotic episodes is a therapeutic effect. Sedation that occurs with treatment of non acute psychosis disorders, or excessive sedation at any time, is an adverse reaction etc. Observe for adverse effects Excessive sedation is most likely to occur during the first few days of treatment of an acute psychosis episode, when large doses are usually given. Psychotics also seem sedated because the drug lets them catch up on psychosis-induced sleep deprivation. Observe for drug interaction Additive ant cholinergic effects, especially with Thioridazine. Apparently these two drug groups inhibit the metabolism of each other, thus prolonging the actions 198 Psychiatric Nursing of both groups if they are given concomitantly. To avoid low blood pressure, dizziness, and faintness, which may occur in standing To avoid falls or other injuries Dryness of mouth which can predispose to mouth infection, dental cavities, and ill fitting dentures.