Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

AIMS: KCNJ11-related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls. METHODS: Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 patients with KCNJ11 mutations with (n = 9) and without (n = 14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. RESULTS: Patients with KCNJ11-related diabetes without global developmental delay had significant differences compared with sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 patients with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours, and there were also significant deficits in all subdomains of daily living skills. CONCLUSIONS: This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11 diabetes and is the first to compare outcome with sibling controls. Our data demonstrate the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes.

Psychiatric morbidity in children with KCNJ11 neonatal diabetes.

AIMS: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic KATP channel, cause neonatal diabetes. KCNJ11 is also expressed in the brain, and ~ 20% of those affected have neurological features, which may include features suggestive of psychiatric disorder. No previous studies have systematically characterized the psychiatric morbidity in people with KCNJ11 neonatal diabetes. We aimed to characterize the types of psychiatric disorders present in children with KCNJ11 mutations, and explore their impact on families. METHODS: The parents and teachers of 10 children with neonatal diabetes due to KCNJ11 mutations completed the Strengths and Difficulties Questionnaire and the Development and Wellbeing Assessment. Strengths and Difficulties Questionnaire scores were compared with normative data. Diagnoses from the Development and Wellbeing Assessment were compared with known clinical diagnoses. RESULTS: Strengths and Difficulties Questionnaire scores indicated high levels of psychopathology and impact. Psychiatric disorder(s) were present in all six children with the V59M or R201C mutation, and the presence of more than one psychiatric disorder was common. Only two children had received a formal clinical diagnosis, with a further one awaiting assessment, and the coexistence of more than one psychiatric disorder had been missed. Neurodevelopmental (attention deficit hyperactivity disorder and autism) and anxiety disorders predominated. CONCLUSIONS: Systematic assessment using standardized validated questionnaires reveals a range of psychiatric morbidity in children with KCNJ11 neonatal diabetes. This is under-recognized clinically and has a significant impact on affected children and their families. An integrated collaborative approach to clinical care is needed to manage the complex needs of people with KCNJ11 neonatal diabetes.

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations.

OBJECTIVE: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.

Epilepsy drugs may reduce method effectiveness.

PIP: Anticonvulsant drugs used to treat epilepsy have been linked to an increased risk of birth defects among infants of epileptic mothers. Thus, effective contraception for epileptic women is especially important. Copper IUDs, voluntary sterilization, and correct use of barrier methods have been suggested. Most hormonal methods raise concerns, however. Some antiepileptic drugs (e.g., phenytoin, phenobarbital, carbamazepine, and paramethadione) may cause more rapid metabolism of the progestin or estrogen component of combined oral contraceptives. This, in turn, may reduce contraceptive effectiveness, resulting in pregnancy and exposure of the fetus to the potential teratogenic properties of the anti-seizure drug. Since anticonvulsant drugs also speed the metabolism of levonorgestrel, Norplant is not recommended for epileptic women. Depo-Provera is an appropriate method for epileptic women and may reduce seizure frequency.^ieng

Chronic diseases and contraceptive use.

PIP: Barrier methods of contraception and natural family planning may pose unacceptable risks of unintended pregnancy for women with medical conditions in which pregnancy could be dangerous. Although more effective at preventing pregnancy, hormonal methods may affect the course of a chronic disease. The table that comprises this article outlines contraceptive choices and contraindications for women with the following diseases: breast cancer; endometrial, ovarian, and cervical cancer; deep venous thrombosis/pulmonary embolism; hypertension (past, moderate, or severe); diabetes (with and without vascular disease); liver disease; epilepsy; headache; and sickle cell disease.^ieng

Fast action saves lives.

PIP: Health workers trained in emergency care procedures can save children's lives. Appropriate emergency care for children who arrive at the hospital involves organizing this care within hospital routines, identifying and immediately tending to children with life-threatening conditions, and monitoring, further assessing, and modifying treatment where needed. Ways to organize emergency care include frequently checking the line of children waiting for hospital admission to identify and give priority to the very sick; establishing part of the pediatric ward for emergency care and care of very sick children; regularly making sure that essential equipment, oxygen, and drugs are available, and ready for use; adopting standard treatment guidelines for common childhood illnesses and determining whether staff abide by them; placing easy-to-read charts on key treatment guidelines on the wall of the emergency treatment care area; and organizing the hospital for round the clock admission of emergency cases. Health workers can remember the signs and symptoms indicating a life-threatening condition as ABCD (Airway, Breathing, Circulation, and neurological Danger signs). The presence of any of these signs requires immediate action by the senior health worker available. Health workers should check the blood sugar levels of any child requiring emergency care. In areas endemic to malaria, they should also check for malaria parasites. Once immediate care has been given, health workers must closely monitor very sick children until the clinical conditions stabilize. A monitoring chart for each child should be at the child's bed. In the case of convulsions or unconsciousness, health workers should turn the child on his/her side and, if secretions are interfering with breathing, use suction to clear them. If a child suffering from convulsions or unconsciousness also has cyanosis or the convulsions last more than 5 minutes, oxygen must be delivered to the child. Drug treatment (usually diazepam) must be administered if convulsions last more than 5 minutes. If an unconscious child is in shock, intravenous fluids must be administered.^ieng

[Cognitive deficit assessment in asymptomatic HIV-infected females]. / Avaliacao de deficit cognitivo em portadores assintomaticas do virus da imunodeficiencia humana.

PIP: A sample of 16 asymptomatic female HIV carriers (in CDC stages I and II) infected heterosexually and a sample of 26 seronegative women hospitalized in Porto Alegre were studied in order to determine the nervous system manifestations of HIV infection. They answered the computerized version of the Wisconsin Card Sorting Test (WCST) to ascertain how the frontal lobe and the frontotemporal connection were functioning. There was a significant difference between cases and controls (p = 0.0132) with respect to the level of education. The cases performed worse in all measured parameters than the controls (p = 0.0060). The cases made a higher number of total errors (p = 0.00060), a higher percentage of perseverative errors (p = 0.00148) and nonperseverative errors (p = 0.0133). In order to find out whether a possible confounder was at play in the educational level, a stratified analysis was carried out. There was a significant difference between them regarding the total number of errors at the third grade educational level. Differences also appeared at the third grade level with regard to perseverative errors. There was also a significant difference between the two groups in the total number of errors (p 0.05) and perseverative errors (p 0.01) at the level of university education. Multivariate analysis (ANOVA) indicated that age did not alter either the percentage of errors or the number of perseverative responses. The level of education was of importance, but diagnosis was more important to the effect that it was significant in the multivariate equation. With respect to nonperseverative errors, which was altered by the level of education, this factor was isolated as the most important one which maintained significance in this type of analysis. This pilot project should be expanded in the future by applying neuropsychometric tests and depression and anxiety scales in order to confirm the validity of this evaluation.^ieng

Environmental lead hazard to children.

PIP: Clinically evident lead poisoning is rare in Indian children but is more common than in adults. In children, lead poisoning may appear as fever, seizures, anemia, or abdominal pain, while in adults it is more likely to manifest as chronic minor peripheral neuropathy or gum pigmentation. Children with acute lead poisoning can be treated with chelators such as EDTA and BAL, but many are left with permanent brain damage. The most common sources of acute lead poisoning in Indian children are inhalation of fumes from burned car batteries, ingestion of flaking paint, consuming food cooked in cheap aluminum or brass utensils, and eating contaminated soil. The sources of chronic lead poisoning are water from lead pipes and fumes from industrial or automotive exhaust. Another common source in India is application of "kajjal" to children's eyes. Sources of lead in Western countries, such as drinking water, canned food, residential paint, automotive fuel, and ambient air quality, are regulated by law. None of these are regulated in India.^ieng

Problems of hearing impaired children and suggested solutions.

PIP: Factors related to development of verbal skills in hearing-impaired children include early diagnosis, early age of obtaining hearing aids, and early intervention. The development of speech occurs in the first 2 years of one's life. In addition to the hearing aid the child should also get early stimulation and training by parents and professionals toward developing speech and language. The hearing-impaired child is likely to get the benefit of a hearing aid only if it amplifies sound in accordance with his or her hearing loss. Proper audiological examination assesses the level of hearing loss and helps select a suitable hearing aid by conducting an aided audiogram. Parents who accept their child's problem are in a better emotional state to assist their child. The relationship between the degree of hearing impairment and development of verbal skills is analyzed by performance on the verbal section of the Weschler Intelligence Scale for Children (WISC). Analysis of WISC results showed that in a group of 24 children with severe to profound hearing loss only 12% were able to answer questions on the verbal section of WISC. These children were attending normal schools and had developed almost normal speech and language with high parental involvement. In a group of 16 children with moderate and conductive hearing loss 80% were able to deal with the verbal section. Hearing-impaired children who attend school have better prospects of receiving structured stimulation for language development. There are only 2 special schools available for 3-5 year old children in Delhi. Services could be improved by spelling out in the educational policy of training programs for teachers of hearing-impaired children that 1) the method of teaching must be decided on the basis of the hearing-impaired child's capabilities and 2) teachers must conduct proper auditory stimulation programs.^ieng

Early detection and early intervention of hearing handicapped children.

PIP: Early detection means the detection of hearing impairment in an infant under 2 years of age. It is vital as language and other sound-related mental development takes place within the first 3 years of life, and delay leads to secondary disabilities. The delay in language development may be observed by attentive parents at 10-12 months of age and by some not until 3-4 years of age. The family physician often detects a false-positive response, and a child specialist's opinion often is not much different. Most ear, nose, and throat departments have some provisions for audiological testing, however, the audiological section's role is to identify and assess cases for middle ear surgery. Early intervention consists of 1) the provision of amplification, 2) medical assistance, and 3) educational assistance. Pre school programs are held in nursery day schools where deaf children are given 4 hours of daily assistance for 3 years preparing them for placement in the ordinary hearing school in Class I. Special schools for the deaf in India include 1) oral schools without individual hearing aids but with group hearing aids, 2) oral and aural schools with individual hearing aids and group hearing aids, and 3) combined method schools without individual hearing aids and with or without group hearing aids. The evaluation of a program in New Delhi, after its 6 years of existence, sought to identify the strong points and weaknesses in the management of deaf children. This role model was disseminated through 4 series of Max Mueller Bhavan's All India Workshops for parents and teachers of hearing impaired children held at New Delhi, Bombay, Madras, Bangalore and Calcutta between 1981 and 1985. The parents and the professionals who attend these courses publicize them further. Many of them visited the programs in New Delhi with the desire to establish this role model in their school or city.^ieng

Early intervention programme for hearing impaired children.

PIP: The School for Young Deaf Children was founded in 1969 when the All India Institute of Speech and Hearing at Mysore and the Christian Medical College Hospital at Vellore started diagnosing hearing impairment in children and prescribing hearing aids. These schools admitted children when they were 5 years old. Bala Vidyalaya was funded as an experimental school to satisfy the needs of younger children. A multi sensory approach based on the Montessori method of teaching with special emphasis on language acquisition was adopted. The School that began with 5 children and 2 teachers had 120 children and 15 teachers in 1992: 50 children were under 3 years old and the rest were between 3 and 6 years. Early auditory management and training is the foundation of the child's linguistic achievement which help the child use the innate ability to develop sophisticated listening skills such as listening to one signal in the presence of competing sounds. Simple games captivate the infants. At the age of 2 1/2 years ideovisual reading is introduced to the child: written sentences are presented to the child about an activity that the child had just experienced. Even before 2 years of age he or she starts scribbling. School lessons are used as tools for writing. The school takes efforts to win the confidence of the parents. So far 97 children have joined the mainstream of education after an initial training the school. Of these, 6 are settled in jobs, 5 are in college or in postgraduate studies, 11 are studying at the university, 8 are in the higher secondary school (classes XI or XII)m 28 are studying in high school (class VI to class X), while the remaining 39 are in primary schools. It has been demonstrated that early educational intervention and involvement of the family into the educational program are very important for the successful integration of hearing-impaired children into the main stream.^ieng

Leprosy: an urgent need to step up use of MDT in Africa.

PIP: 10-12 million people in the world have leprosy. India claims about 4 million of these cases. Overall at least 20% of the cases are children. In the 1940s, dapsone was the only drug used to treat leprosy. By the early 1970s, dapsone did not perform as expected and Mycobacterium leprae were beginning to exhibit resistance to dapsone. In 1982, WHO published results of its study which recommended fixed and relatively short duration regimens of multiple drug therapy (MDT) for all people with leprosy. It also listed recommendations on diagnosis, classification, and distribution of patients to either pauci or multibacillary groups. MDT depends on what type of leprosy patients have. For example, patients with multibacillary leprosy receive rifampicin, clofazimine, and dapsone whereas those with paucibacillary leprosy receive only rifampicin. In many African countries, however, MDT is not used. Yet cases of leprosy exist in 94% of Africa's countries. Moreover 37% have highly prevalent leprosy and the lowest percentage of patients on MDT (18% vs. world average of 56%). In fact, Nigeria is included in the group of 5 countries with 84% of all cases. Until the various countries in Africa can satisfy the ideal requirements for establishing a MDT program, they should begin MDT at least on a small scale. They do need, however, an adequate supply of the drugs. The other requirements include a good plan of action, laboratory facilities, transport, and referral centers. If the period of time needed to meet these requirements is long, then physicians should conduct pre MDT screenings to diagnose cases and determine who needs chemotherapy. The best way to diagnose cases is from clinical experience and paying particular attention to dermatological and neurological findings. Early identification is needed since leprosy cases are stigmatized. This article includes MDT dosages in adults and children.^ieng

Diagnosis of tuberculosis in children.

PIP: Diagnosis of tuberculosis (TB) in children is usually based on presumptions from several elements: clinical picture and course, x-rays, tuberculin test, and culture of pathology later on. TB is usually found in a child because of symptoms of primary disease, or through case-finding of a contact. TB is children is often a primary infection and may be gradual or acute in onset. Some of the symptoms of primary TB are low-grade fever, pallor, fatigue, and anorexia. The child may have erythema nodosum, a yellow module on the conjunctiva, hilar or mediastinal lymphadenopathy, a primary TB complex on the lung (3-10 mm), segmental density, or a positive PPD test. Children with pulmonary disease do not have adult-type cavity lesions, but may have a primary cavity that drains into the bronchi, mechanical complications, fistulas, or atelectasis. Acute TB often appears as meningitis. The pathognomonic signs are cerebrospinal fluid high in lymphocytes with very high albumin (0.6-2 g) and low glucose (0.4-0.2 g/l). TB organisms are rarely seen, but may be cultured. TB meningitis is also notable for choroidal tubercles, which are yellow nodules visible in the fundus. These presumptive signs, as well as increasing neurological findings, prompt immediate treatment. Children also may have acute miliary TB, marked by high fever, gastrointestinal symptoms, hepatosplenomegaly, dyspnea, cyanosis, and respiratory distress, with characteristic diffuse grainy spots on the chest x-ray. A child may have both conditions and may also have localized TB infection elsewhere. Thus, clinical findings may point to possible cultures of urine, gastric lavage, pleural fluid or biopsy, pericardial fluid, bone marrow, or ascitic fluid, any of which should be cultured to rule out other causes. The most common sites for extra-pulmonary TB are cervical nodes, spine, knee. shoulder, hip and peritoneum. Pelvic and urinary tract infections are rare in children.^ieng

Postischemic treatment with hypothermia improves outcome from incomplete cerebral ischemia in rats.

It is known that hypothermia can improve outcome when induced during ischemia. We evaluated whether hypothermia can decrease ischemic injury if it is induced after incomplete ischemia. Rats were anesthetized with 1.4% inspired isoflurane, and ischemia was produced by right carotid ligation combined with hemorrhagic hypotension to 30 mm Hg for 30 min. Hypothermia (31 degrees C) was induced or normothermia (37 degrees C) was maintained for 1 h after completion of the ischemic challenge. Isoflurane anesthesia was maintained during this period. Five of 15 normothermic rats and 3 of 15 hypothermic rats died of stroke after ischemia. For all rats tested, hypothermic-treated animals had a significantly better neurologic outcome than normothermic rats (p less than 0.05). Histopathology showed a correlation of r = 0.67 (p less than 0.05) with neurologic outcome, and neuronal damage was significantly worse in normothermic compared with hypothermic rats (p less than 0.05). These results show that postischemic hypothermia will decrease neuronal injury and improve neurologic outcome associated with incomplete ischemia.

Impact of the environment on reproductive health.

PIP: The WHO workshop on the impact of the environment on reproductive health is summarized. Topics include the nature of environmental factors affecting reproductive health, environmental factors blamed for declining sperm quantity and quality, the effects of natural and man-made disasters on reproductive health, chemical pollutants, how the environment damages reproductive health, and research needs for better research methodologies and surveillance data. Recommendations are made to: 1) promote international research collaboration with an emphasis on consistency of methodological approaches for assessing developmental and reproductive toxicity, on development of improved surveillance systems and data bases, an strengthening international disaster alert and evaluation systems; 2) promote research capabilities for multidisciplinary studies, for interactive studies of the environment and cellular processes, and for expansion of training and education; and 3) take action on priority problems of exposure to chemical, physical, and biological agents, of exposure to pesticides among specific populations, and of inadequate screening methods for identification of environmental chemicals. The costs of environmental injury to reproduction include subfertility, intrauterine growth retardation, spontaneous abortion, and various birth defects. Developed country's primary threats are from chemical pollution, radiation, and stress. There is a large gap in knowledge. Caution is urged in understanding the direct relationship between environmental causes and infertility. Sexual health is difficult to assess and research is suggested. Exposure to excessive vitamin A and toxic chemicals are cited as agents probably having serious effects on malformations. Sperm quality has declined over the decades; there is speculation about the potential causes. The effects of radiation such as at Chernobyl are described. Toxic chemical exposure such as in Bhopal, India killed thousands. Neurological damage is reported for fetuses and infants exposed to methyl mercury. There is the beginning of evidence that complications of pregnancy may be related to pollution levels surrounding industrial plants. Reproductive health is affected through chromosome damage and cell destruction, prenatal death, altered growth, fetal abnormalities, postnatal death, functional learning deficits, and premature aging.^ieng

[Accidents linked to traditional treatment of convulsions of infants and children in Benin]. / Les accidents lies au traitement traditionnel des convulsions du nourrisson et de l'enfant au Benin.

PIP: Convulsions represent a frequent pediatric emergency in southern Benin and Nigeria, where they are estimated to occur in 15% of hospitalizations. The principal cause is fever during a malarial attack. The health team provides symptomatic treatment and searches for the etiology so that adequate treatment can be provided. For the family faced with convulsions, the major concern is to bring the child out of the convulsive state at almost any price. The 3 products most commonly used by parents and other caretakers are cod liver oil, honey, and lemon, which are administered orally often in combination in hopes of provoking vomiting or stimulating the child to regain consciousness. Other substances sometimes administered include cow or cat urine, garlic or onion, and rubbing alcohol. Articles such as spoons or sticks or fingers may be used in attempts to loosen the jaws and avoid blockages. Flagellation may be used to revive the child. Scarification or fumigation may be done to combat sorcery or chase away evil spirits. A hand or leg may be plunged into boiling water or fire to revive the child from a postconvulsive coma. Use of these techniques explains the high rate of mortality or morbidity following convulsions, Morbid states induced by traditional treatments of convulsions may include false bronchial route, ocular or cutaneous burns buccal lesions, injuries to the nasal cavities or lips, and edema of the cheeks. A survey of parents indicated that 37% of families interviewed had been present at a convulsive crisis of their children or siblings. Convulsions were considered a natural ailment by only 55% and a sign of sorcery and malediction by 36%. 84% of parents surveyed knew about possible sequelae of traditional treatments and 40% used them. 90% of families knew about possible sequelae of traditional treatments but explained them by the seriousness of the convulsions or sorcery. 69% felt that more adequate treatment should be found. The best preventive measures would be to prevent malaria and fevers which are the main causes of convulsions. Parents should be taught to substitute intrarectal administration of diazepam if needed and that most crises terminate spontaneously within a few minutes. Children with convulsions should be placed in the lateral position to avoid inhalation of secretions, and should be brought to the nearest health center.^ieng