N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

Background & objectives: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Methods: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. Results: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Interpretation & conclusions: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

Minimal hepatic encephalopathy: diagnosis by neuropsychological and neurophysiologic methods.

Minimal hepatic encephalopathy (mHE) consists of cognitive deficits found on neuropsychological and/or neurophysiologic methods in patients with liver disease, present most commonly in cirrhosis. Patients suffering from mHE may have psychomotor slowing and cognitive deficits affecting their ability to perform many activities of daily life, especially driving and other activities requiring subtle cognitive abilities. It has been now been shown that patients with mHE improve after treatment with agents like lactulose and other therapeutic interventions. Neuropsychological and neurophysiologic tests have been widely used and have shown the greatest promise for the detection of mHE. Commonly used psychometric tests include trailmaking tests (number and figure connection tests) and Wechsler Adult Intelligence Scale (WAIS) for verbal and performance skills. Among the various neuropsychological or psychometric tests, trailmaking tests and block design and digit symbol tests from WAIS-performance battery appear to be adequate for diagnosis of mHE. Standardized tests including NCT A and B, line tracing, serial dotting test and digits-symbol test (PSE syndrome test) validated in German patients need validation in other populations. Both exogenous evoked potentials and endogenous event-related potentials have been used extensively in diagnosing mHE. However, the event-related P300 wave is the most consistent wave and can be considered the electrophysiological counterpart of the psychometric tests as both involve active use of the cognitive faculties. Other new tests like the critical flicker frequency have shown some promise but further studies are required to substantiate initial results. In conclusion, a combination of at least two psychometric (trailmaking tests [NCT or FCT], block design and digit symbol test) and neurophysiological tests (P300 auditory evoked potential or electroencephalography with mean dominant frequency) appears to be optimal in detecting mHE.

Anti-epileptic drugs.

As a sizeable population is affected by epilepsy, so its effective management is a matter of concern. Newer anti-epileptic drugs are now in use, aimed at controls of seizure with fewer side-effects over and above the conventional anti-epileptic drugs. The anti-epileptic drugs can be divided in two groups--conventional anti-epileptic drugs and newer anti-epileptic drugs. The drugs which fall in the first group are--phenytoin, phenobaibitone, valproic acid, carbamazepine, ethosuximide and clonazepam. The second group of drugs are--lamotrigine, clobazam, oxcarbazepine, topiramate and gabapentin. The pharmacology of the drugs are described in a nutshell in this article.