Mitochondrial disease mimicking Charcot-Marie Tooth disease.

Charcot-Marie tooth disease (CMT) is a heterogenous group of peripheral neuropathies caused by various genetic defects. Three cases of mitochondrial myopathy, neuropathy and gastrointestinal encephalopathy (MNGIE) which initially presented with a peripheral neuropathy resembling CMT are described here. The diagnosis in all three cases was made after they developed eye signs and abdominal complaints. Young patients with mutation negative CMT should be followed up to monitor for signs of MNGIE.

Parkinsonism-hyperpyrexia syndrome: the role of electroconvulsive therapy.

Herein, we present a case of a parkinsonism-hyperpyrexia syndrome (PHS) in a 58-year-old man with a 10-year history of Parkinson's disease. The patient presented with a 2-week history of fever and increasing confusion, in the context of a number of changes to his medication regimen. On presentation, he was noted to be febrile with autonomic instability, diaphoresis and marked rigidity. He was disoriented and responding to visual hallucinations. Investigations revealed an elevated creatine kinase and a provisional diagnosis of PHS was made. After the patient failed to respond during a 2-week period to supportive measures, electroconvulsive therapy (ECT) treatment was commenced. A good response to eight bilateral ECT treatments was achieved, with resolution of his confusional state and associated psychotic phenomena. We discuss the nosological and management issues associated with this case and discuss the role of ECT as a treatment modality in this condition.

Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke.

BACKGROUND: Patients with ischaemic stroke due to occlusion of the basilar or vertebral arteries may develop a rapid deterioration in neurological status leading to coma and often to death. While intra-arterial thrombolysis may be used in this context, no randomised controlled data exist to support its safety or efficacy. METHODS: Randomised controlled trial of intra-arterial urokinase within 24 h of symptom onset in patients with stroke and angiographic evidence of posterior circulation vascular occlusion. RESULTS: Sixteen patients were randomised, and there was some imbalance between groups, with more severe strokes occurring in the treatment arm. A good outcome was observed in 4 of 8 patients who received intra-arterial urokinase compared with 1 of 8 patients in the control group. CONCLUSIONS: These results support the need for a large-scale study to establish the efficacy of intra-arterial thrombolysis for acute basilar artery occlusion.

Stereochemistry in clinical medicine: a neurological perspective.

Stereoisomers are compounds that have identical sets of atoms configured in the same positions but are arranged differently spatially. Approximately 25% of contemporary drugs are marketed and used as racemates (i.e., as equimolar mixtures of stereoisomers). This may have major clinical implications, as stereoisomers may possess qualitative and/or quantitative differences in pharmacological effects, plasma protein and tissue binding, metabolic and renal clearance. There are many examples of racemic drugs manufactured and used as single stereoisomers in the field of neurology including the anti-Parkinsonian drugs levodopa, selegiline, apomorphine and entacapone, the antiepileptic drugs tiagabine and levetiracetam, the secondary stroke prevention agent clopidogrel and the acetylcholinesterase inhibitor rivastigmine. The role of drug stereochemistry in the re-evaluation of established drugs and the production of new agents is becoming increasingly important as pharmaceutical companies endeavour to show proof of "no penalty" for the introduction of a racemic new drug over one or other of its single stereoisomers.

Prolonged thiopentone infusion for neurosurgical emergencies: usefulness of therapeutic drug monitoring.

Serial serum thiopentone concentrations were measured during and following completion of an intravenous infusion of thiopentone in 20 patients with neurosurgical emergencies. The concentration data from a further 55 patients who had had some such measurements were reviewed retrospectively. The patients received an infusion for longer than 24 hours at a rate adjusted to maintain EEG burst suppression. The data were interpreted in terms of thiopentone pharmacokinetics and used to produce statistical models relating to clinical outcomes. In these patients, the one-month mortality rate following commencement of thiopentone treatment was 20%; the mean durations of pupillary and motor unresponsiveness following cessation of an infusion were 22 and 91 hours, respectively. Predictors of a prolonged duration of motor unresponsiveness included a prolonged duration of pupillary unresponsiveness, a low thiopentone clearance and a high maximum serum concentration of thiopentone. From pooled logistic regression, median effective serum thiopentone concentrations (EC50) were found to be 50 mg x l(-1) for recovery of pupillary responsiveness and 12 mg x l(-1) for the recovery of motor responsiveness. Because prolonged high-dose thiopentone leads to prolonged residual serum concentrations, it is difficult to distinguish the residual pharmacological effects of thiopentone from the clinical condition. This study suggests that, based on EC50 values for responses, monitoring of post-infusion serum thiopentone concentrations may help determine whether a patient's clinical state is due to residual thiopentone pharmacological effects.

Alterations in cerebral potentials evoked by rectal distension in irritable bowel syndrome.

OBJECTIVE: Central nervous system correlates of the visceral hyperalgesia documented in patients with irritable bowel syndrome are limited. Reproducible cerebral evoked potentials can be recorded in response to rhythmic balloon distension of the rectum in healthy adults. Irritable bowel syndrome patients and healthy subjects were studied to compare the characteristics of mechanically-evoked rectal cerebral potentials obtained during fasting and after the ingestion of a standard meal. METHODS: Twenty-two pairs of age-matched healthy female subjects and female irritable bowel syndrome patients were studied. Cerebral evoked potentials were recorded in response to rhythmic rectal distension (two distension series each of 100 repetitions at 0.8 hertz); cerebral evoked potential recordings were repeated after a 1000 kcal (46% fat) liquid meal. Trait and state anxiety questionnaires were also completed. RESULTS: Compared to healthy subjects, irritable bowel syndrome patients demonstrated higher prevalence of cerebral evoked potential early peaks (latency < 100 ms) postprandially, and uniformly shorter cerebral evoked potential latencies both before and after feeding. CONCLUSION: These findings provide further objective evidence for defective visceral afferent transmission in irritable bowel syndrome patients.

Epilepsy.

Epilepsy may be associated with major social and medical problems, and counselling of patient and family is essential for good management. The workup of a person with a seizure includes history, physical examination, and laboratory testing. An electroencephalogram is essential to help classify the seizure and epilepsy type. Neuroimaging (preferably by magnetic resonance imaging) helps to exclude a structural abnormality. Seizures can be controlled with a single drug (monotherapy) in 70% of patients. The incidence of drug side effects is increased if more than one drug is used. Pregnancy is associated with an increased risk of seizures in 30% of women with epilepsy. Frequent assessment throughout pregnancy is important. There is a slightly increased risk of congenital malformation associated with the antiepileptic drugs. Folic acid supplementation is advisable.

Postoperative seizure outcome in a series of 114 patients with supratentorial arteriovenous malformations.

The incidence of de novo and ongoing postoperative seizures and factors implicated in an increased likelihood of seizures following supratentorial cerebral arteriovenous malformation (AVM) resection remain controversial. We investigated the frequency, severity and variables associated with postoperative seizures in 114 consecutive patients who underwent complete surgical excision of supratentorial AVMs at our institution. The minimal follow up period was 24 months. The incidence of seizures post-AVM surgery was 21% (less than half that found preoperatively). The incidence of postoperative seizures first manifesting >12 months post-AVM resection was 6.3%. A history of preoperative seizures was associated with an increased likelihood of multiple (> or =4) seizures >1 month post-AVM resection (chi2 = 4.38, P = 0.04). Poor functional neurological outcome at 12 months was also a risk factor for the development of > or =1 postoperative seizure using logistic regression analysis (P = 0.04, odds ratio 1.52, 95% CI 1.01-2.28). Cessation of AED therapy in all patients who remain seizure-free at 12 months post-AVM resection is appropriate due to a low risk of new seizure onset or seizure recurrence.

Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy.

BACKGROUND: Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. METHODS: Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. RESULTS: Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. CONCLUSION: The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

Stereoselective interaction of thiopentone enantiomers with the GABA(A) receptor.

1. As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the approximately 2 fold greater potency for CNS effects of (-)-S- over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABA(A) receptor, the primary receptor for barbiturate hypnotic effects. 2. Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABA(A) receptor subtype alpha1beta2gamma2 to determine relative differences in potentiation of the GABA response by rac-, (+)-R- and (-)-S-thiopentone, and rac-pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. 3. With 3 microM GABA, the EC50 values were (-)-S-thiopentone (mean 26.0+/-s.e.mean 3.2 microM, n=9 cells) >rac-thiopentone (35.9+/-4.2 microM, n=6, P=0.1) >(+)-R-thiopentone (52.5+/-5.0 microM, n=8, P<0.02) >rac-pentobarbitone (97.0+/-11.2 microM, n=11, P<0.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC50 values for (+)-R- or (-)-S-thiopentone. 4 Uninjected oocytes responded to >100 microM (-)-S- and R-thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2-bis(2-aminophenoxy)ethane-N, N,N1,N1-tetraacetic acid (BAPTA), a Ca2+ chelating agent. With BAPTA, the EC50 values were (-)-S-thiopentone (20.6+/-3.2 microM, n=8) <(+)-R-thiopentone (36.2+/-3.2 microM, n=9, P<0.005). 5 (-)-S-thiopentone was found to be approximately 2 fold more potent than (+)-R-thiopentone in the potentiation of GABA at GABA(A) receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo.

Transient visual obscurations and headache in aqueduct stenosis exacerbated by menstruation.

The influence of female sex hormones is implicated in the pathogenesis of benign intracranial hypertension, but their effect on intracranial pressure (ICP) in other settings is not known. We report a 23-year-old white female with catamenial exacerbations of transient visual obscurations and headache suggestive of raised ICP. The patient had obstructive hydrocephalus secondary to stenosis of the aqueduct of Sylvius associated with a Chiari type I malformation. Exacerbation of raised ICP during the menstrual period was the most likely cause of her symptoms. Female sex hormones may influence the secretion or absorption of cerebrospinal fluid in conditions other than BIH.

Is Sydenham's chorea an antiphospholipid syndrome?

In 1686, Thomas Sydenham described a syndrome of chorea occurring in youth which was subsequently shown to be a complication of rheumatic fever. An association between chorea and antiphospholipid antibodies has been reported since 1985. We report two females presenting with chorea, aged 17 and 22, who fulfilled the Jones' criteria for rheumatic fever and concurrently had antiphospholipid antibodies detected in serum. A third patient presented at the age of 16 with two bouts of Sydenham's chorea; no assays for antiphospholipid antibodies were performed at the time but 13 years later she was found to have high titres of anticardiolipin antibodies. No patient had abnormalities in the basal ganglia detected on magnetic resonance imaging. Sydenham's chorea may be part of the spectrum of antiphospholipid-associated neurological disease.

Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone.

AIMS: Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(-)- enantiomers, until very recently, have been largely ignored. METHODS: The present study analyses the pharmacokinetics of R-(+)- and S-(-)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension. RESULTS: The mean total body clearance (CLT) and apparent volume of distribution at steady-state (Vss) showed trends towards higher values for R-(+)- than for S-(-)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(-)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(-)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(-)-thiopentone was greater than for R-(+)-thiopentone (P = 0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(-)-thiopentone (P = 0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete. CONCLUSIONS: The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(-)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.

Studies on the renal excretion of the acyl glucuronide, phenolic glucuronide and sulphate conjugates of diflunisal.

1. In five healthy male volunteers given multiple doses of diflunisal (DF), renal clearances (CLR) of the acyl glucuronide (DAG), phenolic glucuronide (DPG) and sulphate (DS) conjugates were about 42, 25 and 13 ml min-1, respectively. 2. These relatively low CLR values are probably due largely to the very high plasma protein binding of the conjugates, found in vitro to be 99.0%, 97.8% and 99.45%, respectively. 3. Thus glomerular filtration plays the minor and active tubular secretion the major role in renal excretion of the three conjugates. 4. This conclusion was supported by the effect of probenecid co-administration, which decreased CLR of DAG and DPG by about 70%. CLR for DS could not be calculated when probenecid was co-administered (because of interference by probenecid metabolites in the analysis of DS in urine). 5. Water-induced diuresis had no effect on CLR of the DF conjugates, consistent with tubular reabsorption being negligible.

Patterns of seizure occurrence in catamenial epilepsy.

The pattern of seizure occurrence was analysed over 44 menstrual cycles in 12 epileptic women who considered they had menstrually related seizures. Two peaks in the daily seizure rate were apparent. A significant increase in seizures occurred during the days of menstrual flow and the two days preceding it, with a second peak in the four days at midcycle. The lowest seizure rate was in the late phase of the menstrual cycle. Daily salivary progesterone levels were assayed in 11 women, and 12 ovulatory and eight anovulatory cycles were identified on this basis. No increase in seizures occurred at midcycle if ovulation did not occur, but the perimenstrual increase took place irrespective of ovulatory status.

Effects of antiepileptic drug treatment on the background frequency of EEGs in epileptic patients.

The effect of changing antiepileptic drug concentrations within the therapeutic range on the EEGs of epileptic subjects was studied by quantitative EEG analysis. Twenty-seven patients had administration of one or more drugs discontinued on admission to the hospital for prolonged video/EEG monitoring, and drug levels were correlated daily with the simultaneous EEG background. Phenytoin, alone or in combination with other drugs, led to significant changes in the mean EEG background frequency and increased the percentage of power in the theta and delta bands. In the plasma ranges studied, carbamazepine, phenobarbital, and valproic acid did not lead to significant change in the EEG background frequency; however, the number of subjects taking these medications was small.

EEG monitoring during angiographic balloon test carotid occlusion: experience in sixteen cases.

Ipsilateral hemispheric ischaemia related to permanent or temporary arterial occlusion at the time of operation is a potential risk of surgery upon some aneurysms or tumours which involve the internal carotid artery. Presurgical evaluation of the risks of temporary or permanent internal carotid artery occlusion may help predict patients in these circumstances at risk of stroke. Balloon test occlusion studies involve the elective preoperative occlusion of the internal carotid artery by a deflatable balloon inserted into the cerebral circulation under angiographic control. We have performed 16 balloon test occlusion studies; 2 subjects developed clinical and electroencephalographic changes when the carotid artery was temporarily occluded, and these changes reverted to normal when the balloon was deflated. The results of the test occlusion studies helped in planning the surgical management of all the subjects involved.