Kalpathy S. Krishnamoorthy

AHI1 gene mutations cause specific forms of Joubert syndrome–related disorders

Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain‐hindbrain “molar tooth” sign, a finding shared by a group of Joubert syndrome–related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown.

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature.

Isolated sulfite oxidase deficiency is a rare but devastating neurologic disease that usually presents in early infancy with seizures and alterations in muscle tone. Only 21 cases have been reported in the literature. We report a case of a newborn infant boy with isolated sulfite oxidase deficiency who presented with generalized seizures on his fourth day of life. Plasma total homocysteine was not detectable. Urinary sulfite, thiosulfate, and S-sulfocysteine levels were elevated. The patient began a low-methionine and low-cysteine diet and was treated with thiamine and dextromethorphan. However, he became increasingly microcephalic and was severely developmentally delayed. Mutation analysis of the sulfite oxidase gene revealed that the patient was homozygous for a novel 4-base pair deletion, and both of his parents were found to be heterozygous carriers of the same deletion. We reviewed the clinical, biochemical, neuroradiologic, and neuropathologic features in all published cases of isolated sulfite oxidase deficiency. Seizures or abnormal movements were prominent features in all cases. Developmental delays were reported in 17 cases. Ectopia lentis was detected in 9 cases. Clinical improvement with dietary therapy was seen in only 2 patients, both of whom presented after the age of 6 months and had relatively mild developmental delays. Plasma or urinary S-sulfocysteine levels were elevated in all cases. Urinary sulfite was detected in all except 1 case. Cerebral atrophy and cystic encephalomalacia were observed with neuroradiologic imaging and were noted in all 3 postmortem reports of isolated sulfite oxidase deficiency. The main alternative in the differential diagnosis of isolated sulfite oxidase deficiency is molybdenum cofactor deficiency.

Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up ☆

The EEG features and clinical correlates were investigated before, directly after, and on long-term follow-up after initiation of pyridoxine therapy in 6 patients with B6-dependent epilepsy. At each phase, the EEG provided important diagnostic and prognostic information. Pre-B6 3 neonates manifested a unique EEG pattern of generalized bursts of 1-4 Hz sharp and slow activity. This pattern has not been previously described in neonates with B6 dependency and in this age group appears to be highly suggestive of the diagnosis. Five patients experienced an apparent initial response to traditional antiepileptics. The parenteral pyridoxine test, performed in all 5, and repeated in 3, proved to be a highly reliable and reproducible diagnostic test. After 50-100 mg of B6 there was cessation of clinical seizures within minutes and of paroxysmal discharges within hours. On long-term follow-up (3-28 years) all 6 patients were seizure free on B6 (10-100 mg/day) monotherapy. Recurrences of seizures and of specific sequential EEG changes (background slowing, photoparoxysmal response, spontaneous discharges, stimulus-induced myoclonus, generalized seizures) occurred upon B6 withdrawal. Long-term prognosis correlated with the EEG. Two patients had persistently abnormal EEG backgrounds and were moderately to severely retarded, while 4 had normal EEGs with normal or near normal development.

Cranial Ultrasound Lesions in the NICU Predict Cerebral Palsy at Age 2 Years in Children Born at Extremely Low Gestational Age

Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.

Physical and psychosocial burden due to lymphatic filariasis as perceived by patients and medical experts

Patients with lymphatic filariasis (LF) face considerable physical, psychological and social disabilities. Morbidity management and control are important components of the Global Programme to Eliminate Lymphatic Filariasis. But information on the various disabilities caused by LF is scanty. We measured the severity levels of seven health states of LF in the physical and psychosocial domains of health from the perspective of patients and medical experts, using a 7‐domain 5‐level (7D5L) descriptive system. Adenolymphangitis had the highest severity levels in all domains of health followed by lymphoedema grade 4 (L4), lymphoedema grade 3 (L3), hydrocele grade 2 (H2), lymphoedema grade 2 (L2), lymphoedema grade1 (L1) and hydrocele grade 1 (H1). People with higher grades of lymphoedema and hydrocele had more severe psychosocial problems than physical ones. Severity levels assessed by medical experts were lower than those reported by sufferers. These findings indicate that LF has considerable impact on the physical, mental and social domains of health. Morbidity management programmes should be broadened to include counselling, rehabilitation and health education to manage the psychosocial problems caused by LF.

The dynamics of Wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India.

This paper presents a model-based analysis of longitudinal data describing the impact of integrated vector management on the intensity of Wuchereria bancrofti infection in Pondicherry, India. The aims of this analysis were (1) to gain insight into the dynamics of infection, with emphasis on the possible role of immunity, and (2) to develop a model that can be used to predict the effects of control. Using the LYMFASIM computer simulation program, two models with different types of immunity (anti-L3 larvae or anti-adult worm fecundity) were compared with a model without immunity. Parameters were estimated by fitting the models to data from 5071 individuals with microfilaria-density measurement before and after cessation of a 5-year vector management programme. A good fit, in particular of the convex shape of the age-prevalence curve, required inclusion of anti-L3 or anti-fecundity immunity in the model. An individuals immune-responsiveness was found to halve in approximately 10 years after cessation of boosting. Explanation of the large variation in Mf-density required considerable variation between individuals in exposure and immune responsiveness. The mean life-span of the parasite was estimated at about 10 years. For the post-control period, the models predict a further decline in Mf prevalence, which agrees well with observations made 3 and 6 years after cessation of the integrated vector management programme.

Increased cerebral blood volume and oxygen consumption in neonatal brain injury

With the increasing interest in treatments for neonatal brain injury, bedside methods for detecting and assessing injury status and evolution are needed. We aimed to determine whether cerebral tissue oxygenation (StO2), cerebral blood volume (CBV), and estimates of relative cerebral oxygen consumption (rCMRO2) determined by bedside frequency-domain near-infrared spectroscopy (FD-NIRS) have the potential to distinguish neonates with brain injury from those with non-brain issues and healthy controls. We recruited 43 neonates ≤15 days old and >33 weeks gestational age (GA): 14 with imaging evidence of brain injury, 29 without suspicion of brain injury (4 unstable, 6 stable, and 19 healthy). A multivariate analysis of variance with Newman–Keuls post hoc comparisons confirmed group similarity for GA and age at measurement. StO2 was significantly higher in brain injured compared with unstable neonates, but not statistically different from stable or healthy neonates. Brain-injured neonates were distinguished from all others by significant increases in CBV and rCMRO2. In conclusion, although NIRS measures of StO2 alone may be insensitive to evolving brain injury, increased CBV and rCMRO2 seem to be useful for detecting neonatal brain injury and suggest increased neuronal activity and metabolism occurs acutely in evolving brain injury.

Detailed semiautomated MRI based morphometry of the neonatal brain: Preliminary results

In the neonate, regional growth trajectories provide information about the coordinated development of cerebral substructures and help identify regional vulnerability by identifying times of faster growth. Segmentation of magnetic resonance images (MRI) has provided detailed information for the myelinated brain but few reports of regional neonatal brain growth exist. We report the method and preliminary results of detailed semiautomated segmentation of 12 normative neonatal brains (gestational age 31.1-42.6 weeks at time of MRI) using volumetric T1-weighted images. Accuracy was confirmed by expert review of every segmented image. In 5 brains, repeat segmentation resulted in intraclass correlation coefficients >0.9 (except for the right amygdala) and an average percent voxel overlap of 90.0%. Artifacts or image quality limited the number of regions segmented in 9/12 data sets and 1/12 was excluded from volumetric analysis due to ventriculomegaly. Brains were segmented into cerebral exterior (N = 8), cerebral lobes (N = 5), lateral ventricles (N = 8), cerebral cortex (N = 6), white matter (N = 6), corpus callosum (N = 7), deep central gray (N = 8), hippocampi (N = 8), amygdalae (N = 8), cerebellar hemispheres (N = 8), vermis (N = 8), midbrain (N = 8), pons (N = 8) and medulla (N = 8). Linear growth (P < 0.05) was identified in all regions except the cerebral white matter, medulla and ventricles. Striking differences in regional growth rates were noted. These preliminary results are consistent with the heterochronous nature of cerebral development and provide initial estimates of regional brain growth and therefore regional vulnerability in the perinatal time period.

THE EPIDEMIOLOGY OF GERMINAL MATRIX HEMORRHAGE DURING THE FIRST HALF‐DAY OF LIFE

The personal and maternal characteristics of 27 babies with early‐onset germinal matrix hemorrhage (EGMH) were compared with those of 280 babies with normal cranial ultrasonograms, studied in a separate clinical trial. None of the mothers of the babies with EGMH had high blood pressure or pre‐eclampsia during pregnancy. Gestational age <30 weeks and initial pH <7·2 indicated increased risks of EGMH, and maternal receipt of steroids indicated reduced risk of EGMH. Thus prenatal and immediately perinatal factors appear to convey much of the information about the risk of EGMH.

Video and CD-ROM as a Training Tool for Performing Neurologic Examinations of 1-Year-Old Children in a Multicenter Epidemiologic Study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals. (J Child Neurol 2005;20:829—831).