Blood heavy metal levels in children with attention deficit hyperactivity disorder: an unsolved enigma

Background: The role of heavy metals in the etio-pathogenesis of attention deficit hyperactivity disorder (ADHD) is a burning enigma. The available studies with discordant results are from different geographical localities with different monitoring, regulations and sociocultural backgrounds. The differential association of heavy metals with ADHD severity and phenotypes has not been adequately examined. Also, there are concerns about laboratory quality control. Therefore, the present case control study was formulated.Methods: Thirty children with ADHD diagnosed by DSM IV criteria and thirty group age matched controls were enrolled. Detailed perinatal, past, developmental and possible exposure history to various heavy metals was taken. Severity of ADHD was assessed using ConnersTM Parent reporting questionnaire. Blood level of metals was estimated by inductively coupled plasma- atomic emission spectroscopy (ICP-AES).Results: The mean blood lead, mercury, cadmium, arsenic, zinc were comparable in children with ADHD and group age matched controls. The mean blood lead, mercury and cadmium levels in study population was higher than found in studies from developed countries. Elevated arsenic, mercury and cadmium were found in both cases and controls. Blood zinc correlated significantly with inattention T score and blood mercury with hyperactivity-impulsitivity T score of Conners parent rating scale. Blood cadmium was present in greater proportion of predominant hyperactive-impulsive type patients.Conclusions: Zinc deficiency correlates with inattention; cadmium and mercury toxicity correlate with hyperactivity. Mean blood levels of heavy metals is elevated in a substantial proportion of study population. So, there is an urgent need for sensitization and environmental control.

Postnatal Maturation of Amplitude Integrated Electroencephalography (aEEG) in Preterm Small for Gestational Age Neonates

Objective: The primary objective was to evaluate the postnatal maturation pattern on aEEGduring first two weeks of life in clinically stable and neurologically normal preterm small forgestational age (PSGA) and gestation matched (1 week) preterm appropriate for gestationalage (PAGA) neonates born between 300/7 and 346/7 weeks of gestation. Methods: SerialaEEG tracings were recorded on 3rd, 7th and 14th day of life. The primary outcome wastotal aEEG maturation score. Three blinded assessors assigned the scores. Results: Weanalyzed a total of 117 aEEG recordings in 40 (19 PSGA and 21 PAGA) neonates. Thebaseline characteristics were comparable except for birthweight [1186 (263) vs 1666(230) g]. There was no difference in the mean (SD) total scores on day 3 (9.0 (1.8) vs. 9.5(1.1), P=0.32) and day 14 of life, but was lower in PSGA infants on day 7 (8.6 (2.4) vs. 10.1(1.1), P=0.02). On multivariate analysis, maturation of PSGA neonates was found to besignificantly delayed at any point of life from day 3 to day 14 (mean difference, -0.8, 95 % CI:-1.6 to -0.02, P=0.04). Conclusion: Lower aEEG maturation score on day 7 possiblyindicates delayed maturation in PSGA neonates in the first week of life.

INCLEN Diagnostic Tool for Neuromotor Impairments (INDT-NMI) for Primary Care Physician: Development and Validation.

Objectives: To develop and validate a diagnostic tool for use by primary care physicians for diagnosing neuro-motor impairment among 2-9 year old children in primary care settings. Study design: Modified Delphi technique involving national (n=49) and international (n=6) experts was used for development of INDT-NMI. The tool was then validated through a cross sectional study. Setting: Neurology specialty clinics of three tertiary care pediatric centers in New Delhi, India. Participants: 454 children aged 2-9 years [mean (SD) age: 60.4 (23.7) mo], selected through systematic random sampling, underwent assessment for identification and classification of neuromotor impairments (NMI). Intervention: All study subjects were first administered INDTNMI (candidate test) by a trained physician followed by expert assessment for NMI and other neurodevelopment disorders (NDD) by team of two pediatric neurologists (Gold standard). Results: According to expert evaluation, 171 (37.8%) children had neuromotor impairments. There were four categories of subjects: NMI alone (n=66); NMI+other NDDs (n=105); Other NDDs without NMI (n=225) and ‘Normal’ group (n=58). Using expert evaluation as gold standard, overall sensitivity of the INDTNMI was 75.4% and specificity was 86.8%. INDT-NMI helped graduate physicians to correctly classify 86.6% (112/129) children with NMI into different types (cerebral palsy, neuromotor diseases and other NMI). Graduate physicians assigned 40 children (8.8%) as ‘indeterminate’, 38 (95%) of whom had either NDD and/or NMI and thus merited referral. Misclassification of NMI occurred in those with mild changes in muscle tone, dystonia, or ataxia and associated NDDs. Conclusion: Graduate primary care physicians with a structured short training can administer the new tool and diagnose NMI in 2-9 year old children with high validity. INDT-NMI requires further evaluation in actual primary care settings.

INCLEN Diagnostic Tool for Epilepsy (INDT-EPI) for Primary Care Physicians: Development and Validation.

Objective: To evaluate the diagnostic accuracy of a new diagnostic instrument for epilepsy – INCLEN Diagnostic Tool for Epilepsy (INDT-EPI) – with evaluation by expert pediatric neurologists. Study design: Evaluation of diagnostic test. Setting: Tertiary care pediatric referral centers in India. Methods: Children aged 2-9 years, enrolled by systematic random sampling at pediatric neurology out-patient clinics of three tertiary care centers were independently evaluated in a blinded manner by primary care physicians trained to administer the test, and by teams of two pediatric neurologists. Outcomes: A 13-item questionnaire administered by trained primary care physicians (candidate test) and comprehensive subject evaluation by pediatric neurologists (gold standard). Results: There were 240 children with epilepsy and 274 without epilepsy. The candidate test for epilepsy had sensitivity and specificity of 85.8% and 95.3%; positive and negative predictive values of 94.0% and 88.5%; and positive and negative likelihood ratios of 18.25 and 0.15, respectively. Conclusion: The INDT-EPI has high validity to identify children with epilepsy when used by primary care physicians.

INCLEN Diagnostic Tool for Attention Deficit Hyperactivity Disorder (INDT-ADHD): Development and Validation.

Objective: To develop and validate INCLEN Diagnostic Tool for Attention Deficit Hyperactivity Disorder (INDT-ADHD). Design: Diagnostic test evaluation by cross sectional design. Setting: Tertiary care pediatric centers. Participants: 156 children aged 65-117 months. Methods: After randomization, INDT-ADHD and Connor’s 3 Parent Rating Scale (C3PS) were administered, followed by an expert evaluation by DSM-IV-TR diagnostic criteria. Main outcome measures: Psychometric evaluation of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. Results: INDT-ADHD had 18 items that quantified symptoms and impairment. Attention deficit hyperactivity disorder was identified in 57, 87 and 116 children by expert evaluation, INDT-ADHD and C3PS, respectively. Psychometric parameters of INDT-ADHD for differentiating attention deficit hyperactivity disorder and normal children were: sensitivity 87.7%, specificity 97.2%, positive predictive value 98.0% and negative predictive value 83.3%, whereas for differentiating from other neuro-developmental disorders were 87.7%, 42.9%, 58.1% and 79.4%, respectively. Internal consistency was 0.91. INDT-ADHD has a 4-factor structure explaining 60.4% of the variance. Convergent validity with Conner’s Parents Rating Scale was moderate (r =0.73, P= 0.001). Conclusions: INDT-ADHD is suitable for diagnosing attention deficit hyperactivity disorder in Indian children between the ages of 6 to 9 years.

INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): Development and Validation.

Objective: To develop and validate INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD). Design: Diagnostic test evaluation by cross sectional design Setting: Four tertiary pediatric neurology centers in Delhi and Thiruvanthapuram, India. Methods: Children aged 2-9 years were enrolled in the study. INDT-ASD and Childhood Autism Rating Scale (CARS) were administered in a randomly decided sequence by trained psychologist, followed by an expert evaluation by DSM-IV TR diagnostic criteria (gold standard). Main outcome measures: Psychometric parameters of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. Results: 154 children (110 boys, mean age 64.2 mo) were enrolled. The overall diagnostic accuracy (AUC=0.97, 95% CI 0.93, 0.99; P<0.001) and validity (sensitivity 98%, specificity 95%, positive predictive value 91%, negative predictive value 99%) of INDT-ASD for Autism spectrum disorder were high, taking expert diagnosis using DSM-IV-TR as gold standard. The concordance rate between the INDT-ASD and expert diagnosis for ‘ASD group’ was 82.52% [Cohen’s κ=0.89; 95% CI (0.82, 0.97); P=0.001]. The internal consistency of INDT-ASD was 0.96. The convergent validity with CARS (r = 0.73, P= 0.001) and divergent validity with Binet-Kamat Test of intelligence (r = -0.37; P=0.004) were significantly high. INDT-ASD has a 4-factor structure explaining 85.3% of the variance. Conclusion: INDT-ASD has high diagnostic accuracy, adequate content validity, good internal consistency high criterion validity and high to moderate convergent validity and 4-factor construct validity for diagnosis of Autistm spectrum disorder.

Management of Raised Intracranial Pressure.

Appropriate management of raised intracranial pressure begins with stabilization of the patient and simultaneous assessment of the level of sensorium and the cause of raised intracranial pressure. Stabilization is initiated with securing the airway, ventilation and circulatory function. The identification of surgically remediable conditions is a priority. Emergent use of external ventricular drain or ventriculo-peritoneal shunt may be lifesaving in selected patients. In children with severe coma, signs of herniation or acutely elevated intracranial pressure, treatment should be started prior to imaging or invasive monitoring. Emergent use of hyperventilation and mannitol are life saving in such situations. Medical management involves careful use of head elevation, osmotic agents, and avoiding hypotonic fluids. Appropriate care also includes avoidance of aggravating factors. For refractory intracranial hypertension, barbiturate coma, hypothermia, or decompressive craniectomy should be considered.

Approach to the Child with Coma.

Coma and other states of impaired consciousness represent a medical emergency. The potential causes are numerous, and the critical window for diagnosis and effective intervention is often short. The common causes of non-traumatic coma include central nervous system infections, metabolic encephalopathy (hepatic, uremic, diabetic ketoacidosis etc.), intracranial bleed, stroke and status epilepticus. The basic principles of management include 1) Rapid assessment and stabilization, 2) Focussed clinical evaluation to assess depth of coma, localization of lesion in the central nervous system and possible clues to etiology, and 3) Treatment including general and specific measures. Commonly associated problems such as raised intracranial pressure and seizures must be recognized and managed to prevent secondary neurologic injury.

Efficacy of Pyridoxine in Early-Onset Idiopathic Intractable Seizures in Children.

Objective To identify pyridoxine responsive seizures among children with early onset intractable seizures, and to identify pyridoxine-dependency as a subset in this group. Methods Patients with neonatal onset idiopathic, intractable seizures were identified over a 6-month period and subjected to a ‘pyridoxine trial’, at the Pediatric Neurology Clinic of a tertiary-care teaching hospital in New Delhi, India. This consisted of an intravenous infusion of 100 mg of pyridoxine over 10-min with a simultaneous EEG monitoring. This procedure was carried out in the EEG laboratory with all appropriate precautions (including availability of resuscitation Results 621 children with active epilepsy were seen at the PNC, of which 48 had early-onset, medical intractable epilepsy, and 21 children (13 males and 8 females), aged between 11 month and 38 month were enrolled. The median age at onset of seizure was 5.1 months. The major seizure type was focal in 3 and generalized in 18 (including infantile spasm in 11). No patient had normalization of EEG during the ‘trial’. Two patients (9.5%) had a response during the 2 weeks of oral treatment and oral therapy was continued. No toxicity or side-effects of pyridoxine were observed in these two patients over a follow-up of more than 18 months. Conclusions Pyridoxine responsive seizures contribute a significant proportion to early-onset idiopathic intractable epilepsy in childhood. Routine use of pyridoxine in the management of early onset resistant seizures would go a long way in identifying these patients early.

Aetiology of global developmental delay in young children: Experience from a tertiary care centre in India.

Background. Global developmental delay is a common reason for referral to a paediatrician. We examined the aetiological yield of an extensive diagnostic work-up in young children with developmental delay in a tertiary referral centre. Methods. To assess the diagnostic possibilities, we systematically examined 100 consecutive children with global developmental delay (<5 years of age) who visited the paediatric outpatient department over a period of 18 months. An association between the presence of features at initial contact and aetiology was analysed by the 2-tailed Fisher exact test and chi-square test. Results. Of the 100 children, 65 were <2 years of age (mean age 23.6 months) at presentation. The presence of birth asphyxia, sepsis, seizures, abnormal neurological findings, and dysmorphism were significant predictors of aetiology. Four diagnostic categories—chromosomal disorders including Down syndrome, hypoxic–ischaemic encephalopathy, multiple malformation syndromes and cerebral dysgenesis—were the most common causes of global development delay in 20%, 15%, 14% and 11%, respectively. Moderate delay was seen in 42%, severe in 33% and mild in 25% of the patients. The aetiological yield did not differ with the severity of global developmental delay. Additional investigations such as neuroimaging, cytogenetic analysis, metabolic tests and specific molecular tests contributed to a diagnosis in 73% of the children, while in 23% these were the sole means of arriving at a diagnosis. Neuroimaging for a specific indication was almost twice more likely to yield an aetiology when compared with neuroimaging performed as a screening tool (65% v. 35%; p=0.003). Conclusion. The aetiological yield in this selected cohort with global developmental delay was 73%. A step-wise investigational approach is justified in all children with developmental delay, regardless of the severity of delay or the absence of findings on history and physical examination. This study is an attempt to formulate an investigative approach in a child with global developmental delay, especially in developing countries where advanced molecular and cytogenetic studies are not routinely available.

Inflicted neuro-trauma in infancy.

Two infants with non-accidental inflicted neuro-trauma are reported. One presented with sudden onset lethargy, respiratory difficulty and unexplained seizures. There were bilateral retinal bleeds and extradural hemmorage. Other was a well thriving child who had 2 seizures and was noted to lack visual fixation. Retinal hemorrhages and chronic subdural and intraparenchymal hemorrhages were subsequently discovered. We highlight the importance of suspecting child abuse in infants with sudden unexplained unresponsiveness, seizures or respiratory difficulty and the unusual occurrence of extradual hemorrhage.

Subacute Sclerosing Panencephalitis in a Tertiary Care Centre in Post Measles Vaccination Era.

This study was conducted to observe the impact of measles vaccination on the epidemiology of subacute sclerosing panencephalitis (SSPE) in the post measles vaccination era. This is a retrospective study from a tertiary care hospital, covering a ten year period starting a decade after the introduction of the national measles immunization programme in India. We analyzed 458 serologically confirmed SSPE cases. These patients had a high cerebrospinal fluid: serum anti-measles antibody ratio. The male to female ratio in the present study was 4.4:1. The mean age at onset of SSPE was 13.3 years, showing an increase in mean age at onset of SSPE. Clinical and other demographic details, available from 72 in-patients, are discussed in this report. Of these, a history of measles could be elicited in 34 cases. Mean latent period between measles infection and onset of SSPE was 7.8 years. Six patients gave a history of measles vaccination. A sizable percentage (15.5 %) of the patients was ≥ 18 years old and considered to have adult onset SSPE. The incidence of SSPE continues to be high and this report highlights the need for further strengthening routine measles immunization coverage.

Acute bilateral vision loss as the presenting feature of subacute sclerosing panencephalitis.

A 12-yr-old boy with an atypical presentation of subacute sclerosing panencephalitis (SSPE) is described. Bilateral macular chorioretinitis preceded the neurological symptoms by 3 weeks. Both visual and neurological features had an acute onset. Clinicians need to be aware that macular chorioretinitis in a child may be the heralding feature of SSPE.

Outcome in childhood guillain-barré syndrome.

To assess the outcome of children diagnosed with Guillain-Barré syndrome (GBS), followed up for a median duration of 25 months. Methods. Tertiary center, prospective follow up of children with GBS enrolled from Dec 2003 through Sep 2006. Functional recovery was determined at 12 months and later using Hughes scale (0-6). Clinical, electrophysiological variables were compared between the good outcome (grade 0/1) and bad outcome groups (died or functional grade >1). Results. Among 52 children with a median age of five yr there was male preponderance (75.4%). Mortality during acute phase was 11.5% (6/52). Among the survivors long term data was obtainable in 40 of the 46 children. At one year follow up 87.5% children had fully recovered or had minimal symptoms, beyond one year this rose to 95%. Only 2 among 40 had significant symptoms at last follow up (1 grade-2 and 1 grade-3). Factors significantly associated with poor outcome were: need for artificial ventilation, inexitable nerves on nerve conduction testing and delayed independent walking. Conclusion. Children needing ventilation have the worst short-term prognosis. However, irrespective of severity during acute phase, good long-term recovery can be expected in most children.

Autosomal recessive type I lissencephaly.

Lissencephaly (LIS) is a brain malformation manifested by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration, excluding polymicrogyria and other cortical dysplasias. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy. It may have familial occurrence and can occur in sibs of same family often leading to a diagnostic problem. Several lissencephaly syndromes have been described. Here a familial syndrome of lissencephaly is reported. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation cannot be excluded.

SCIWORA-Spinal Cord Injury Without Radiological Abnormality.

Following trauma, the commonly used radiological investigations, plain radiographs and computed tomography (CT) studies do not rule out injury to the spinal cord. This is especially true for children, as an entity known by the acronym SCIWORA (spinal cord injury without radiological abnormality) exists and the changes may be picked up only on magnetic resonance imaging (MRI). Early treatment (within 6 hours) with high dose methylprednisolone improves the outcome. Spinal trauma being common it is possible that the burden of neurological handicap following this can be reduced by increasing awareness and early treatment with steroids. In the community, pediatricians are often the first medical contact after spinal trauma and awareness of the lacune of conventional imaging techniques is important especially if clinical symptoms pertaining to the spine are present. The community pediatrician is hereby made aware of the need to investigate spinal trauma with a MRI for possible SCIWORA situation as it generates a possibility for therapeutic intervention to alter the outcome positively.