Biomedical subjects
Publications and source records attributed to S Jawad.
A 22-year-old patient with partial seizures developed schizophreniform psychosis following the introduction of vigabatrin. She stopped her anticonvulsant medication as a consequence of her persecutory delusions. She subsequently suffered status epilepticus with severe brain damage. It is essential to outline a management plan for patients to detect and treat vigabatrin-induced psychosis.
Startle disease, or hyperekplexia, is characterized by an exaggerated startle reflex and neonatal hypertonia. An autosomal dominant form of the disorder is associated with mutations in the same codon of the alpha 1 subunit of the inhibitory glycine receptor (GLRA 1) resulting in the substitution of an uncharged amino acid for Arg271 in the mature protein. However, recessive transmission is seen in the mouse mutant spasmodic which resembles startle disease phenotypically and is also associated with mutations in Glra 1. We have confirmed the finding of Arg271 mutations in individuals with startle disease in a UK family showing autosomal dominant transmission. In addition we describe an apparently sporadic case, the offspring of a consanguineous mating, who is homozygous for a novel mutation (T1112A) in GLRA 1, which results in the substitution of asparagine for isoleucine at position 244 of the mature protein. This suggests that human startle disease can display recessive as well as dominant inheritance resulting from different mutations in GLRA 1.
To elucidate the natural course of the nephropathy associated with penicillamine and thereby facilitate its clinical management 33 patients with rheumatoid arthritis who developed proteinuria during treatment with oral penicillamine were studied in detail throughout their renal illness. Renal biopsies were performed, and creatinine clearance and proteinuria were measured serially for 74 months (range 16-148 months). Fourteen patients developed proteinuria within six months after the start of treatment and 27 within 12 months. When treatment was stopped the proteinuria reached a median peak of 4.2 g/24 h (range 0.3-15.0 g/24 h) at one month (range 0-7 months) before resolving spontaneously by six months (12 patients), 12 months (21), or 18 months (29). In all patients but one, who developed carcinoma of the renal pelvis, proteinuria resolved by 21 months and its median duration was eight months. The median first and last measurements of creatinine clearance showed no appreciable change (80 ml/min and 78 ml/min), and no patient died from or needed treatment for renal failure. The HLA-B8 or HLA-DR3 alloantigen, or both, were identified in 10 patients. Renal biopsy specimens showed membranous glomerulonephritis in 29 patients, minimal change nephropathy in two, and electron dense deposits in the mesangial regions in two. In all the patients whose nephropathy was due solely to treatment with penicillamine the proteinuria resolved completely when the drug was withdrawn; renal function did not deteriorate, and corticosteroids were unnecessary.
Retrospective comparison of peripheral haematological values in normal volunteers and patients on anti-epileptic drugs over a one year period demonstrated a significant reduction in total white blood cells, neutrophil, eosinophil, lymphocyte and monocyte counts in patients. The red blood cell count, mean cell volume and mean cell haemoglobin were significantly reduced in the patients. These findings need to be taken into account when new anti-epileptic drugs are assessed by adding on to existing therapy.
Twenty-three residential patients on chronic antiepileptic drugs (AEDs) were entered into an open study of 4 weeks duration. Baseline variables and seizure frequency were determined in the first week. All patients received a single dose of lamotrigine in the second week to determine single-dose pharmacokinetic parameters. Twenty patients then received daily or twice daily lamotrigine for a week. Post-treatment seizure frequency was observed for a further week. Patients taking liver enzyme inducing antiepileptic drugs showed a mean lamotrigine plasma elimination half-life (T1/2) of 14 h (+/- 7) (T1/2 of normal volunteers = 24 h) and those taking sodium valproate and an inducing AED showed a mean lamotrigine T1/2 of 30 h (+/- 10). The plasma concentrations of co-administered sodium valproate, phenytoin, carbamazepine, phenobarbitone and primidone were not altered by 1 week lamotrigine dosing. There was a significant reduction in complex partial seizures in the treatment week compared with baseline. Some patients showed a marked increase in seizure frequency on stopping lamotrigine. There was an increase in reports of drowsiness during lamotrigine administration, but there were no clinically significant changes in any safety measure.
Lamotrigine, a novel anticonvulsant, has been evaluated in patients with epilepsy using the method of interictal EEG spike counting. In a randomised double-blind trial it was found that oral lamotrigine (240 mg) was more effective than placebo, but less effective than diazepam (20 mg) in suppressing interictal spikes. Further clinical evaluation of lamotrigine is recommended in patients with epilepsy.
Midazolam is a water soluble 1,4 benzodiazepine which is suitable for intramuscular administration. It is currently used for pre-medication and the induction of anaesthesia. Its antiepileptic properties have been evaluated by studying its effect on interictal spikes on the EEG of six adult epileptic patients. The results indicate that intramuscular midazolam 15 mg is more effective than intramuscular diazepam 10 mg in abolishing interictal spikes and as effective as intravenous diazepam 20 mg five minutes after administration.
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The pharmacokinetics of clobazam were studied in six healthy volunteers and six age and sex matched enzyme-induced epileptic patients. In the epileptic patients the area under the plasma concentration-time curve for clobazam was significantly smaller and the area under the plasma concentration-time curve for N-desmethylclobazam was significantly greater than in the healthy volunteers. Plasma N-desmethylclobazam concentrations were found to be much higher than those of clobazam in the epileptic patients, raising the possibility that the antiepileptic properties of clobazam are to be attributed more to its metabolite than the parent drug.
The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.