Etiología y evolución de recién nacidos con hipotiroidismo congénito y glándula eutópica / Etiology and evolution of newborns with congenital hypothyroidism and eutopic thyroid gland

RESUMEN Objetivos Analizar las características clínicas, bioquímicas, estudios complementarios, hallazgos moleculares y la prevalencia de glándula eutópica en neonatos con HC pertenecientes al Programa Provincial de Pesquisa Neonatal de Córdoba, Argentina, entre 1996 y 2015. Analizar la evolución de los pacientes que reunieron criterios para una reevaluación. Pacientes y métodos Se analizaron retrospectivamente las historias clínicas de 237 pacientes detectados por pesquisa neonatal en la provincia de Córdoba, Argentina, entre 1996-2015 con una incidencia promedio de 1/2146 pesquisados. Presentaron glándula eutópica 81 pacientes (34%) F35/M46; se excluyeron 10 con síndromes genéticos asociados. Se analizaron los niveles de: TSH, T4T, T4L, T3, TPOAb / TGAb y Tiroglobulina (ECLIA -ROCHE) (VR: >15 días: 6-83 ng/ ml; <15 días: 29-173 ng/ml), ecografía y centellografía de cuello con Tc-99m. El valor de corte de TSH sérica adoptado para la confirmación diagnóstica fue de ≥10 mUI/ml. Se realizaron estudios de biología molecular en casos seleccionados. Se reevaluaron niños mayores de 3 años, sin bocio, con valores normales de Tiroglobulina y sin requerimiento de incrementos en la dosis de LT4. Resultados: La prevalencia de HC y Tiroides Eutópica se mantuvo constante. El 50% de los pacientes (36/71) mostraron hiperplasia glandular tiroidea. El 84% (n: 60 de 71) presentó niveles de TSH sérica ≥20 uUI/ml (20-1186) y el 75% (n: 53 de 71) >40 uUI/ml (40-1186). TGAb and TPOAb fueron positivos en un niño. La determinación de TG fue normal en el 29% (21/71) de los casos, elevada en el 56% (39/71) y baja en el 14% (10/71). Los estudios de biología molecular resultaron diagnósticos en 26 pacientes de 18 familias, demostrándose mutaciones en los genes de: TPO: 9 pacientes, TG: 12 pacientes, NIS: 2 pacientes, DUOX2: 2 pacientes y TRβ: 1 paciente. Se encontraron 11 nuevas mutaciones: tres en TPO, cinco en TG, dos en NIS y una en DUOX2. Se informaron anomalías congénitas en el 11% (8/71) de los pacientes. Se reevaluó el 11% (8/71) de los niños, resultando: HC transitorio n: 5, permanente n: 2 y una niña con Síndrome de Resistencia a las Hormonas Tiroideas. La prevalencia de lactantes con HC y glándula eutópica se mantuvo constante a lo largo de 19 años del Programa. Conclusiones Nuestros estudios demuestran que la prevalencia de Hipotiroidismo Congénito con glándula eutópica se mantuvo estable en los períodos analizados. Este grupo de pacientes se caracterizó predominantemente por presentar HC de carácter permanente acompañado por fenotipos de moderada a severa intensidad. En el futuro deberá profundizarse el conocimiento respecto a la influencia de factores medioambientales, como posibles agentes de riesgo asociados a la génesis de Hipotiroidismo Congénito.

abstract Objectives To describe clinical, biochemical characteristics and complementary studies to diagnosis, molecular findings and the prevalence of eutopic gland in newborn with CH detected through our neonatal screening program in Córdoba, Argentina, between 1996 and 2015. To analyze the evolution of the patients who met criteria for re-evaluation. Patients and methods We retrospectively analysed medical records of 237 patients with CH detected by neonatal screening in Córdoba, Argentina, from 1996 to 2015 with an average incidence of 1/2146 researched. 81 patients (34%) F35/M46 had eutopic thyroid gland; 10 patients with associated genetic syndromes were excluded. TT4, FT4, T3, TSH, TPOAb, TGAb and Thyroglobulin (VR: >15 days: 6-83 ng/ml; <15 days: 29-173 ng/ml) (ECLIA ROCHE), thyroid ultrasonography and 99Tc scan were assessed. The serum TSH cutoff value adopted for diagnostic confirmation was ≥10 mIU/ml. Molecular biology studies were performed in selected cases. Those who had no goiter, with normal thyroglobulin, and had not required increases in L-T4 dose underwent re-evaluation after the age of 3 years. Results The prevalence of HC and thyroid Eutopic remained constant. 50% of the patients (36/71) showed glandular hyperplasia. In 84% (60/71) presented serum TSH levels ≥20 uUI/ml (20-1186) and in 75% (n: 53 of 71) levels >40 uUI/ml (40-1186). TGAb and TPOAb were positive only in one baby. TG levels were: normal in 29% (21/71) of the cases, elevated in 56% (39/71) and low in 14% (10/71). Gene mutations were found in 26 patients from 18 families: TPO: 9 patients, TG: 12 patients, NIS: 2 patients, DUOX2: 2 patients y TRβ: 1 patient. Eleven new mutations were found: three in TPO, five in TG, two in NIS and one in DUOX2. Congenital anomalies were reported in 11% (8/71) patients. The 11% (8/71) of children were re-evaluated resulting in: 5 Transient CH, 2 Permanent CH and 1 with Resistance to Thyroid Hormones. The prevalence of infants with CH and eutopic gland remained constant along 19 years of the Program. Conclusions Our studies show that the prevalence of congenital hypothyroidism with eutopic gland remained stable in the periods analyzed. This group of patients was predominantly characterized by permanent CH accompanied by moderate to severe phenotypes. In the future, knowledge about the influence of environmental factors, as possible risk agents associated with the genesis of Congenital Hypothyroidism, should be deepened.

Successful extension of assessment and rehabilitation intervention for an adolescent with postcoma multiple disabilities through a learning setup.

Prior to the beginning of this study, the participant (an adolescent with postcoma multiple disabilities) had learned to use a forehead-skin response to access environmental stimuli. These learning data seemed to indicate a minimally conscious state (i.e., awareness of the link between response and stimuli) in spite of 1) a previous diagnosis of postcoma vegetative state; and 2) concomitant electrophysiological measurement showing no evidence of a passive P300 response and of mismatch negativity. The present study was an effort to extend the early learning investigation with two additional responses and related stimuli to broaden learning evidence and ascertain possible choice behavior. Results indicated that the participant learned the new responses and also provided evidence of choice behavior. These data were discussed in terms of the usefulness of the learning paradigm in the assessment and rehabilitation of persons with postcoma multiple disabilities and consciousness disorders.

Effects of ionic and non-ionic paramagnetic contrast media on brain bio-electric activity.

The potential neurotoxic effects of gadolinium (Gd)-based compounds for enhanced MRI are not completely understood. We investigated electroencephalography changes induced by ionic and non-ionic Gd-based compounds administered intravenously in patients affected by lesions of the central nervous system (CNS) characterized by breakdown of the blood-brain barrier. This double-blind, randomized, study of two parallel groups involved 40 patients scheduled for an MRI examination with contrast medium for known CNS lesions. Twenty patients were randomly allocated to receive non-ionic Gd-DTPA-BMA/gadodiamide and 20 patients were randomly allocated to receive ionic Gd-DTPA/gadopentetate. For both groups the intravenous dose was 0.1 mmol/kg body weight. Three electroencephalography recordings were performed: immediately before, during, and 15 min after contrast medium injection. Mean and peak frequencies of the beta band and absolute power of the delta and/or theta bands of the electroencephalograms (EEGs) were noted. Each EEG was also evaluated to detect any alterations. The values of the 8-12 Hz band showed a significant increase during and after injection versus baseline in the gadopentetate group (P<0.05) and a significant decrease during injection in the gadodiamide group (P<0.05). The values of the 12-16 Hz band showed a significant increase versus baseline during and after injection in the gadopentetate group (P<0.05). The electrophysiological method based on computerised spectral analysis is a sensitive tool for evaluating effects of contrast media on brain bio-electric activity. EEG changes are detectable, even in the absence of any clinical evidence. It would appear that there might be clinical advantages in the use of non-ionic compounds.

Review: molecular thyroidology.

Novel disorders involving aberrations of the hypothalamic-pituitary-thyroid gland-thyroid hormone axis have been described in the last 5 to 10 years. The following topics are addressed: molecular mutations causing central hypothyroidism (isolated autosomal recessive TRH deficiency; autosomal recessive TRH-receptor inactivating mutations; TSH beta-subunit bio-inactivating mutations; Pit-1 mutations; Prop1 mutations; high molecular weight bio-inactive TSH); defects in response to TSH (mutations in the TSH receptor: TSH receptor gain-of-function mutations; TSH receptor loss-of-function mutations); defects in thyroid gland formation: transcription factor mutations (TTF-2 and Pax8); defects in peripheral thyroid hormone metabolism (defective intrapituitary conversion of T4 to T3; hemangioma consumption of thyroid hormone); and defects in tissue response to thyroid hormone (generalized thyroid hormone resistance, selective pituitary thyroid hormone resistance). While molecular diagnosis of such conditions is rarely indicated for clinical management, knowledge of the molecular mechanisms of these diseases can greatly enhance the clinical laboratory scientist's ability to advise clinicians about appropriate thyroid testing and to interpret the complex and sometimes confusing results of thyroid function tests.

Information and competency for consent to pharmacologic clinical trials in Alzheimer disease: an empirical analysis in patients and family caregivers.

This study was undertaken to evaluate (1) what information normal and Alzheimer disease (AD) participants are able to manage; (2) the correlation between the degree of competency and age, education and dementia scores, and the ability of dementia scores to predict incompetence; and (3) the capacity to retain consent-related information. To fulfil these aims, a four-point competency rating scale (1 = incompetent, 2 = marginally competent, 3 = sufficiently competent, and 4 = completely competent) was used in 70 patients (Mini-Mental State Examination [MMSE] score >9; Global Deterioration Scale score <6) and in 40 cognitively normal caregivers. Patients were divided into two subgroups (competency ratings 1 and 2 versus 3 and 4) to calculate positive and negative predictive values of MMSE and Alzheimer Disease Assessment Scale-cognitive (ADAScog) for absent/marginal competence. Main results were as follows: (1) 32.9% of AD patients were "incompetent" (no caregivers), 37.1% were "marginally competent" (20% caregivers), 18.6% were "sufficiently competent" (50% caregivers), and 11.4% were "completely competent" (30% caregiverss). (2) Competency ratings and age did not correlate in AD, whereas a negative correlation was significant in caregivers; competency ratings positively correlated to education in caregivers. (3) ADAScog and MMSE were the tests most significantly correlated to competency; MMSE score below 18 had a positive predictive value of 95% and a negative predictive value of 63.3%. The fact that 95% of patients with MMSE scores below 18 are incompetent or marginally competent points to an urgent need for ethical procedures capable of creating a balance between difficulties in obtaining valid consent and a patient's right to benefit from advances in clinical research.

Posttraumatic epilepsy risk factors: one-year prospective study after head injury.

PURPOSE: Prospective evaluation of risk factors for posttraumatic epilepsy (PTE) by using clinical, EEG, and brain computed tomography (CT) data in four assessments from the head injury (HI) acute phase to 1 year later; and evaluation of the possible epileptogenic role of hemosiderin as shown by brain magnetic resonance imaging (MRI). METHODS: Risk factors for PTE were evaluated by using Kaplan-Meier curves, log-rank test, and the Cox model in 137 consecutively enrolled adult inpatients. Percentage differences of patients with brain hyperintense and/or hemosiderin areas shown by MRI 1 year after HI were statistically evaluated by univariate tests considering two subgroups [e.g., patients with (PTE) and without (WLS) late seizures]. RESULTS: The PTE subgroup included 18 patients with at least two seizures between the second and twelfth months. Kaplan-Meier curves demonstrated that Glasgow Coma Scale low score, early seizures, and single brain CT lesions are PTE risk factors, as is the development of an EEG focus 1 month after HI. No significant percentage difference was found between PTE and WLS patients with hemosiderin spots shown by MRI 1 year after HI. CONCLUSIONS: the Cox model indicates that, for HI patients with early seizures and brain CT single temporal or frontal lesions in the acute phase, the PTE risk is 8.58 and 3.43 times higher, respectively, than for those without. An EEG focus 1 month after HI is a risk factor 3.49 times higher than for patients without such EEG changes. One year after HI, a higher percentage of PTE than WLS patients had cortical MRI hyper-intense areas including hemosiderin.

EEG power spectrum differences in early and late onset forms of Alzheimer's disease.

OBJECTIVE: To evaluate the relationship between some EEG spectral parameters and age of onset of Alzheimer's disease (AD). METHODS: A study on the wakefulness EEG, recorded during eyes closed and open, was carried out on 150 AD patients (NINCDS-ADRDA criteria). Fifty-two normal subjects served as controls. RESULTS: A significant prevalence of an EEG spectrum characterised by lack of a dominant peak in the 6.5-12 Hz band was found in early AD (EAD). Age of onset correlated inversely with the 1-6.5 Hz relative powers and positively with 6.5-12 Hz relative powers. A similar correlation was also found when a subgroup of mild initial AD was selected. Moreover, evidence of EEG changes peculiar to early onset AD emerged when 3 subgroups (with age of onset < or =60, range 61-69 and > or =70 years) were compared. CONCLUSION: Irrespective of the severity of disease, this study provides evidence of specific changes of wakeful EEG in patients affected by early-onset AD.

Hippocampus and parahippocampal gyrus linear measurements based on magnetic resonance in Alzheimer's disease.

MRI-based linear measurements of the hippocampus and parahippocampal gyrus complex (HPC) discriminated 39 subjects with probable Alzheimer's disease, from 15 patients with other dementias and 33 miscellaneous controls without evidence of dementia. The best discriminating parameter was the left height of the HPC at the level of the mammillary bodies, with a sensitivity of 79.49% and a specificity of 68.75%. The diagnostic value of these results is discussed considering the volumetric data found in the current literature.

EEG spectral analysis in Alzheimer's disease and different degenerative dementias.

The EEG was recorded in 25 patients with Alzheimer's disease (AD), 25 patients with non-Alzheimer degenerative dementias (NAD), matched for age and severity of dementia and 50 age- and sex-matched normal subjects. The recordings were made with the subjects at rest with eyes closed (REC) and opened (REO). The data was subjected to spectral analysis and the power was computed in five contiguous 5.5 Hz bandwidths in the range 1-28.5 Hz. The present study confirms the consistent prevalence of a spectrum characterised by the lack of a dominant activity in the 6.5-12 Hz band with high power in 1-6.5 Hz band in AD. Moreover quantitative spectral parameters discriminate not only AD from the other groups, but also NAD from age matched normal subjects.

Depression after stroke: an investigation through catamnesis.

BACKGROUND: In the early stage of stroke, depression appears to be linked to certain brain areas. The study evaluated the importance of the side of the lesion in depressed patients 3 years after their first stroke. METHOD: Patients who had suffered a stroke and been discharged after rehabilitation were identified by hospital records. We interviewed 180 patients at home. Demographic as well as socioeconomic data were collected. The North-western University Disability Scale, the Beck Depression Inventory (BDI), the Relatives' Stress Scale, and the Social Dysfunction Rating Scale were applied. The diagnosis was confirmed for each patient by a clinical assessment according to the ICD-10 criteria. Patients with previous psychiatric treatment, comprehension problems, or severe hemi-inattention were excluded. RESULTS: By using a score of 14 on the BDI as a cutoff, 62 patients (34%) proved to be affected by depressive disorders. Clinical records showed that the location of the lesion was in the right hemisphere for 37 patients and in the left hemisphere for 25 patients. Statistical analysis of the mean scores obtained in this subgroup of depressed patients showed (1) no significant relation between depression and the hemispheric location of the lesion or between depression and level of education; (2) relation between BDI score and social activities; and (3) stress on the relatives that was mainly dependent on both the disability of the patients and their loss of social activities, whereas depression played a minor role. CONCLUSION: A high percentage of patients have depressive disorders 3 years or more after the stroke, independent of the side. Such mood disorders worsen the relationship between the disabled patients and their relatives and worsen leisure independent of the affected hemisphere.

Randomised, double-blind, placebo-controlled study of pivagabine in neurasthenia.

One hundred and eighteen patients with neurasthenia, as defined by ICD 10 (International Classification of Diseases), participated in a randomised, double-blind, placebo-controlled trial of pivagabine (4-[(2,2-dimethyl-1-oxopropyl)amino]butanoic acid, CAS 69542-93-4, Tonerg). Pivagabine 1800 mg/d was administered orally for four weeks. At the end of the trial, active medication was significantly superior to placebo on the Clinical Global Impression (CGI) improvement of illness scale. In addition, pivagabine treatment reduced the physical and mental fatigability of patients, and increased their sense of well-being.

EEG power spectrum typical of vascular dementia in a subgroup of Alzheimer patients.

A statistical comparative study was carried out between two subgroups of patients with dementia, i.e. 22 with Alzheimer's dementia (AD, 44% of the entire Alzheimer group examined) and 36 with vascular dementia (VaD, 97% of the entire vascular group). The selection of the two subgroups was based on a similar EEG spectral profile in the rest eyes closed condition: a great increase in low frequency powers and a dominant activity in the 6.5-12 Hz band. The aim was to identify any possible difference between the two groups analysing the spectral descriptors, of the two conditions eyes closed and open, the demographic figures and the mental deterioration scores. The results are as follows: (i) the spectral profiles and their numerical descriptors of the AD subgroup patients are not distinguishable from the same parametric figures of the VaD patients; (ii) the spectral analysis becomes useful in differentiating the two types of dementia when a dynamic EEG is processed, i.e. the power ratio of recordings during eyes closed and open; (iii) a more severe mental deterioration, especially in attention and spatial and temporal orientation was found in the AD group as compared to the VaD. The findings are explained in the light of the changes in neural mechanisms which underlie both the alpha and slow rhythms.

An EEG power index (eyes open vs. eyes closed) to differentiate Alzheimer's from vascular dementia and healthy ageing.

EEG differential power patterns between Alzheimer's (AD, 50 patients) and vascular (VaD, 37 patients) dementia and between these two and 36 healthy ageing subjects, were studied in the 6.5-12 Hz band of the ongoing EEG recorded during the rest eyes closed (REC) and eyes open (REO) conditions. From the EEGs (16 electrodes, 10-20 international system except for Fz, Cz, Pz), a 6.5-12 Hz band, wider than the alpha range (alpha-like), was chosen and processed to include the highest theta frequencies characterising the occipital dominant activity in dementia. A global and occipital EEG Power Index (PI) was calculated and used considering the absolute powers during REC and REO. The MANOVA was used to compare the figures. Bearing in mind that the higher the PI value the greater the difference between the 6.5-12 Hz EEG band powers of REC vs. REO, the results were as follows: (i) in the patients with Alzheimer's and vascular dementia the global and occipital PIs were significantly lower than those in controls; (ii) in the patients with Alzheimer's dementia the same PIs were significantly lower that those of the patients with VaD; (iii) healthy elderly subjects showed significantly lower powers in the 6.5-12 Hz frequencies at T5 and O1 in REO as compared to dementia patients. The pathophysiological implications and the clinical applications of these results are discussed.

EEG spectral analysis in vascular and Alzheimer dementia.

The role of EEG spectral analysis in the diagnosis of syndromes of dementia is still disputed. Since there have been few studies dealing with the profile of power spectra, the present investigation has focused on this aspect, constructing power spectra taken from 16 derivations and calculated by averaging twenty 2 sec epochs, using a serial array of frequencies from 1 to 32 Hz. The spectral analysis of the EEG, recorded under awake resting eyes closed (REC) and open (REO) conditions, was performed in 50 patients with Alzheimer's disease (AD), 37 with vascular dementia (VaD) and 36 elderly controls. Three spectral profiles were found under REC: (i) type A, showing a dominant 6.5-12 Hz peak (44% AD, 97.3% VaD), although lower than in controls; (ii) type B, lacking a dominant peak in the 6.5-12 Hz band, but characterised by high power in 1-6.5 Hz band (44% AD, 2.7% VaD); (iii) type C, corresponding to a flat, low voltage, spectrum (12% AD). Unlike controls, demented patients showed an increased REO/REC power ratio in the 6.5-12 Hz band, especially in those with type B spectra. AD patients with type B spectra had an earlier age of disease onset.

Comparative study of terfenadine and cetirizine in hay fever: assessment of efficacy and central nervous system effects.

A daily dose of either terfenadine 120 mg or cetirizine 10 mg was compared in two parallel groups of patients suffering from hay fever. According to a double-blind, double-dummy, randomized design, 28 patients were treated with one of the two drugs once daily in the morning for 2 weeks during the 1990 grass pollen season. The severity of nasal congestion, rhinorrhea, sneezing, nasopharyngeal itching and itchy, watery, red eyes was evaluated by the investigator after a 1-week run-in period and at the end of the treatment. The patients made a daily record of the severity of symptoms on a diary card. In addition, drug-related central nervous system (CNS) effects were assessed at baseline and at the end of the treatment by neuropsychological tests aimed at investigating selective and sustained attention, visuomotor abilities and anxiety, and by quantitative, bit-mapped EEG. Both terfenadine and cetirizine produced a significant improvement in symptoms at endpoint without any significant difference between the two drugs. Drowsiness was referred by one patient in each treatment group. No significant impairment of psychomotor performance occurred with either drug. Quantitative EEG showed a significant power increase in the relative (%) delta band in both groups of treated patients. Although the difference was not statistically significant, a tendency towards greater involvement of the CNS was observed with the use of cetirizine. In conclusion, the results of this study confirm that terfenadine and cetirizine are equally effective in the management of hay fever. Some differentiated untoward EEG changes were also observed in relation to the drugs used, without any variation in neuropsychological performance.

Promoting ambulation and object manipulation in persons with multiple handicaps through the use of a robot.

A robot was used with a man and a woman affected by blindness, motor disabilities, and mental retardation. The robot was to assist these subjects during their ambulation and allow them to reach a couch (on which to sit) and to transport objects. The data showed that both subjects learned to use the robot, succeeded in transporting and putting away objects, and achieved independent ambulation times of over 22 and 20 min. per session. Staff personnel found the situation in which the subjects were busy with the robot preferable to situations in which the robot was not available.