Adjuvant immunosuppression for paradoxical deterioration in tuberculous meningitis including one case responsive to cyclosporine. A tertiary referral hospital experience.

BACKGROUND: Tuberculous meningitis (TBM) accounts for 1-4% of all tuberculosis (TB) presentations. Paradoxical deterioration in non-HIV patients is a common manifestation of anti-tuberculosis therapy, characterised by clinico-radiological deterioration. We report a case series of TBM admissions to our institution including one case with paradoxical deterioration refractory to corticosteroids who responded to adjuvant cyclosporine. METHODS: Retrospective review of 12 HIV-negative patients admitted to Liverpool Hospital, Sydney (2005-2016) with laboratory and/or radiologically confirmed TBM. RESULTS: Median patient age was 40 (range 22-81 years), M:F = 7:5. Eleven patients (92%) were of Asia-Pacific origin. Eleven initially presented with central nervous system manifestations and one had preceding miliary TB. Nine patients had extra-cranial TB involvement including eight with past or current pulmonary disease. Cerebrospinal fluid (CSF) TB PCR/culture was positive in 10 patients. Paradoxical deterioration developed in three patients despite concomitant corticosteroids in two. One patient with paradoxical deterioration was refractory to corticosteroids: A 22-year-old Vietnamese male with TBM developed worsening headaches and altered mentation after seven weeks concomitant anti-TB and corticosteroid treatment. Interval MRI brain demonstrated increased size and number of tuberculomas as well as hydrocephalus. Cyclosporine was added with gradual improvement and ultimately good outcome. CONCLUSION: Our case series highlights the seriousness of paradoxical deterioration in TBM and the potential role of adjuvant cyclosporine in patients refractory to corticosteroids.

Delayed-onset focal dystonia of the leg secondary to traumatic brain injury.

A 42-year-old man presented with action-induced, stereotyped posturing of the left leg with task specificity following major traumatic brain injury less than a year earlier. Although adult onset primary leg dystonia is a recognised entity, our patient is unusual in that dystonia was an isolated abnormality without associated spasticity, was not preceded by ipsilateral hemiparesis and remained focal without progression to involve other body regions. MRI brain showed a small area of gliosis in the left frontal subcortical white matter but with no lesions in the basal ganglia or thalamus. The dystonia in our patient almost completely resolved with botulinum toxin therapy.

Glyphosate-surfactant herbicide-induced reversible encephalopathy.

Glyphosate-surfactant (GlySH) is a commonly used herbicide that has been used in attempted suicide. Most reports of GlySH toxicity in patients have followed ingestion of the commercial product "Round-up" (Monsanto Ltd; Melbourne, Victoria, Australia), which consists of a mixture of glyphosate (as a isopropylanine salt) and a surfactant (polyoxyethyleneamine). Ingestion of Round-up is reported to cause significant toxicity including nausea, vomiting, oral and abdominal pain. Renal and hepatic impairment and pulmonary oedema may also occur. Impaired consciousness and encephalopathy have been reported as sequelae but there are limited data on the central nervous system (CNS) effects of Round-up toxicity. We report a 71-year-old male who attempted suicide with GlySH and developed a prolonged but reversible encephalopathy suggestive of acute CNS toxicity.

Utility of magnetic resonance imaging in diagnosing ulnar neuropathy at the elbow.

OBJECTIVE: Magnetic resonance imaging (MRI) of the ulnar nerve is being increasingly employed in the diagnosis of ulnar neuropathy at the elbow (UNE). Our aims were to: (i) assess the sensitivity of MRI in diagnosing UNE, especially in cases where neurophysiologic studies were non-localizing, (ii) determine the spectrum of MRI abnormalities in patients presenting with symptoms and signs of ulnar neuropathy, (iii) assess whether MRI findings differ between grades of UNE severity, and (iv) to see if MRI findings give an input into the pathological mechanisms of UNE. METHODS: Clinical, neurophysiologic, and radiologic (MRI) records were reviewed in 52 patients with symptoms and signs of ulnar neuropathy. Ulnar nerve MRI studies were assessed by an unblinded observer. RESULTS: The sensitivity of MRI at diagnosing UNE was higher than conventional nerve conduction studies, 90 versus 65%, respectively. In patients with non-localizing neurophysiologic studies (n=19), MRI disclosed changes consistent with UNE in 16 (84%) cases. The most frequent MRI findings included a combination of high signal intensity and nerve enlargement (63%), followed by nerve compression (27%) and isolated high signal intensity (23%), and isolated nerve enlargement (2%). There was no significant difference between patients with localizing and non-localizing neurophysiologic testing. Lastly, there were no differences between different grades of UNE, suggesting that UNE may be a neurophysiologically heterogeneous disorder. CONCLUSIONS: MRI studies proved to be more sensitive than conventional nerve conduction studies at diagnosing UNE. In addition, the MRI studies were highly sensitive in patients with non-localizing UNE. SIGNIFICANCE: Our study shows that MRI of the ulnar nerve should be used in patients with clinical features of UNE especially in those with non-localizing neurophysiologic testing.

Acute and reversible micrographia in a patient possibly due to cerebral ischaemia.

We report a patient who developed acute and reversible micrographia, presumably due to cerebral ischaemia, on a background of mutism following a pharyngo-laryngectomy 10 years earlier. Magnetic resonance (MR) imaging showed chronic small vessel disease without evidence of an acute ischaemic lesion on diffusion-weighted sequences. Our patient's micrographia improved significantly within 12 days of symptom onset. The MR imaging was performed within 5 days of symptom onset, suggesting that the lesion was either too small for detection or had resolved on diffusion-weighted sequences.

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.

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.

Pretreatment and posttreatment positron emission tomographic scan imaging in a 20-year-old patient with Wilson's disease.

Wilson's disease is an autosomal-recessive inherited disorder that results in predominantly hepatic and neurologic manifestations. Neurologic abnormalities include tremor, ataxia, bradykinesia, rigidity, chorea, and dystonia. We report the clinical, radiologic, and serial FDG PET findings in a 20-year-old woman who presented with an asymmetric upper limb tremor caused by Wilson's disease. Reduced striatal and cerebral cortical glucose metabolism was demonstrated on a FDG PET study performed before the commencement of D-penicillamine therapy. After 6 months of treatment, the patient had shown only minimal clinical improvement, despite an increase in striatal and cerebral cortical glucose metabolism on a repeat FDG PET study. After 14 months of treatment, however, a moderate clinical improvement was noted and there was further increase in glucose metabolism on FDG PET.

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.