Konanki Ramesh

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

ABSTRACT The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 μg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.

SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a South Indian population.

OBJECTIVE To determine the effect of SLCO1B1 gene polymorphisms (rs11045819, rs4149032 and rs4149033) on rifampicin (RMP) concentrations in adult tuberculosis (TB) patients from south India. METHODS We genotyped adult TB patients for three SLCO1B1 gene polymorphisms-rs11045819, rs4149032 and rs4149033-and compared 2-h post-dosing RMP concentrations of the different genotypes for each of the polymorphisms. Plasma RMP was determined using high-performance liquid chromatography. Genotyping was performed using direct sequencing. RESULTS Among the 256 study patients, minor allele frequencies were respectively 0.01 (A), 0.46 (C) and 0.07 (A) for rs11045819, rs4149032 and rs4149033 polymorphisms; genotype distributions followed Hardy-Weinberg equilibrium. RMP concentrations did not significantly differ between the different genotypes of the three polymorphisms. CONCLUSION This is the first study to show that rs11045819, rs4149032 and rs4149033 polymorphisms in the SLCO1B1 gene did not influence RMP concentrations in Indian patients.

Child Neurology: Epilepsy of infancy with migrating focal seizures

Epilepsy of infancy with migrating focal seizures is a rare, infantile epileptic encephalopathy characterized by normal early development, refractory focal seizures arising independently from both hemispheres, and severe psychomotor retardation. In the revised terminology by the International League Against Epilepsy, it has been classified as an “electro-clinical syndrome” of “unknown cause” with onset in infancy.1 Affected infants have progressive psychomotor retardation and decline of head circumference percentile. We present a 6-month-old boy diagnosed with this entity and discuss the approach to an infant with unexplained refractory seizures. A 6-month-old boy presented with developmental delay and focal seizures. He was the second child born to a third-degree consanguineous couple. His perinatal period had been uneventful and he had attained social smile by the age of 6 weeks. He started having seizures at the age of 2 months. The seizures consisted of deviation of eyes and head along with tonic posturing of arm or leg of either side and associated flushing. The seizures usually lasted for 1–2 minutes. The initial frequency was 2–3 per day but gradually over the next 4 months, it increased to 50–60 per day. He had been treated with phenobarbitone, phenytoin, carbamazepine, topiramate, and levetiracetam without success. He had lost social smile, and not gained any new developmental milestones. Family history was not significant. Examination revealed a well-thriving baby with head circumference of 40 cm (<−2 SD). There were no neurocutaneous markers or dysmorphic features. The neurologic examination revealed reduced interaction and alertness, normal cranial nerves including fundus, and normal tone with brisk tendon reflexes and extensor …

Development and validation of AIIMS modified INCLEN diagnostic instrument for epilepsy in children aged 1 month–18 years

OBJECTIVES There is shortage of specialists for the diagnosis of children with epilepsy, especially in resource limited settings. Existing INCLEN (International Clinical Epidemiology Network) instrument was validated for children aged 2-9 years. The current study validated modifications of the same including wider symptomatology and age group. METHODS The Modified INCLEN tool was validated by a team of experts by modifying the existing tools (2-9 years) to widen the age range from 1 month to 18 years and include broader symptomatology in a tertiary care teaching hospital of North India between January and June 2015. A qualified medical graduate applied the candidate tool which was followed by gold standard evaluation by a Pediatric Neurologist (both blinded to each other). RESULTS A total of 197 children {128 boys (65%) and 69 girls (35%)}, with a mean age of 72.08 (±50.96) months, completed the study. The sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio of the modified epilepsy tool were 91.5% (84.5-96.1), 88.6% (80.0-93.5), 89.7% (81.9-95.3), 90.8% (83.7-95.7), 8 (6.6-9.8) and 0.09 (0.07-0.12) respectively. SIGNIFICANCE The new modified diagnostic instruments for epilepsy is simple, structured and valid instruments covering 1month to 18 years for use in resource limited settings with acceptable diagnostic accuracy. All seizure semiologies as well as common seizure mimics like breath-holding spells are included in the tool. It also provides for identification of acute symptomatic and febrile seizures.

Infantile-Onset Alexander Disease A Genetically Proven Case With Mild Clinical Course in a 6-Year-Old Indian Boy

Alexander disease is an autosomal dominant leukoencephalopathy characterized by developmental delay, macrocephaly, and characteristic neuroimaging abnormalities predominantly involving frontal lobes. We report a 6-year-old Indian boy with infantile-onset Alexander disease, who has an unusually mild clinical course and a de novo p.Leu359Val mutation in the glial fibrillary acidic protein gene.

Teaching NeuroImages: Distinct neuroimaging features of fucosidosis

A 5-year-old girl, the product of nonconsanguineous marriage, presented with early-onset intellectual disability and autistic features. There was no regression, seizures, or vision or hearing impairment. She had normal head circumference, coarse facies, angiokeratomas, and lower limb rigidity. She had no cherry-red spot or …

Limb-Girdle Myasthenia Gravis in a 10-Year-Old Girl A Case Report

A 10-year-old girl presented with progressive proximal limb muscle weakness without facial, ocular, or bulbar muscle involvement. There was no fatigability or diurnal fluctuation in symptoms. Her weakness worsened with febrile illnesses and recovered with accruing disabilities over a few weeks. Serum creatine kinase levels and muscle biopsy were normal. A significant decrement on repetitive nerve stimulation test and positive response to therapeutic neostigmine challenge test confirmed the diagnosis of limb-girdle myasthenia. She responded well to corticosteroids and thymectomy, demonstrating a likely autoimmune etiology. This case highlights the long-term fluctuations in a case of myasthenia gravis and the need for a high index of suspicion for myasthenia in children presenting with unexplained muscle weakness, even in the absence of typical features such as fatigability, diurnal fluctuation, and oculobulbar weakness.

Renal agenesis and external iliac artery stenosis in an infant with moyamoya disease.

We describe a 14-month-old girl who presented with arterial ischemic stroke due to moyamoya disease, unilateral renal agenesis and external iliac artery stenosis. The association of moyamoya disease with renal agenesis and external iliac artery stenosis has not been described before. This report expands the spectrum of moyamoya disease and suggests that moyamoya disease may have an intrauterine onset.

Development of All India Institute of Medical Sciences-Modified International Clinical Epidemiology Network Diagnostic Instrument for Neuromotor Impairments in Children Aged 1 Month to 18 Years

Introduction There is shortage of specialists for the diagnosis of children with neuromotor impairments (NMIs), especially in resource limited settings. Existing International Clinical Epidemiology Network (INCLEN) instrument for diagnosing NMI have been validated for children aged 2–9 years. The current study modified the same including wider symptomatology and age group (1 month to 18 years). Methods The Modified INCLEN diagnostic tool (INDT) was developed by a team of experts by modifying the existing tool to widen the age range (1 month to 18 years) and include broader symptomatology (inclusion of milestones from the first 2 years of life and better elucidation of cerebellar and extrapyramidal features) in a tertiary care teaching hospital of North India between January and April 2015. A trained medical graduate applied the candidate tool, which was followed by gold standard evaluation by a Pediatric Neurologist (both blinded to each other). Results A total of 197 children (102 with NMI and 95 without NMI) were enrolled for the study. The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratio of the modified NMI tool were 90.4% (82.6–95.5), 95.5% (88.7–98.7), 95.5% (88.9–98.7), 90.3% (82.4–95.5), 19.9 (12.1–32.6), and 0.13 (0.08–0.12), respectively. Conclusion The All India Institute of Medical Sciences modified INDT NMI tool is a simple and structured instrument covering a wider symptomatology in the 1 month to 18 years age group with acceptable diagnostic accuracy.

Growth of Infants Born to HIV-Infected Women in Madurai, South India

Objective: To compare the growth patterns of HIV-infected and HIV-exposed, uninfected infants. Methods: Design: Prospective cohort study. Setting: Clinic of National Institute for Research in Tuberculosis, Madurai located in the Governement Rajaji Hospital (GRH) campus. Participants: Infants born to HIV-infected women in GRH, Madurai between January 2006 to October 2008. Infants were excluded if they were too ill, or had congenital abnormalities. Intervention: Baseline socio-demographic details and feeding patterns were recorded. Clinical assessment, anthropometric measurement, complete blood count, CD4 and CD8 counts and DNA PCR testing were performed. Anthropometric assessments and immunology profile were repeated once in 3 months till 24 months of age. Main outcome: Rate of change of weight and CD4% in HIV exposed and infected infants. Results: Of 76 infants enrolled, 25 were found to be HIV-infected by DNA PCR and fourteen of them died (11 before their first birthday). Weight gain in HIV-infected infants was 0.144 kg ((95% CI: -0.237, -0.051), P=0.003) less per month compared to negative infants, after adjusting for age, gender and feeding practice. Similarly, when compared to HIV negative infants, the decline in CD4 percentage was 3.1% ((95% CI: -4.735, -1.461), P<0.001) more in HIV positive infants. Changes in height, CD4 count, head circumference and haemoglobin were not associated with HIV status. Conclusion: Growth faltering occurs early in life in HIV-infected infants and its identification is important for developing appropriate treatment and nutritional management strategies. Mortality is high in the absence of early antiretroviral treatment.