Sophie Dethy

PET findings in a brain abscess associated with a silent atrial septal defect

Brain abscesses are classical complications of congenital heart disease (CHD) in children and adolescents. This association is rarely observed in adults. We report a 46-year-old man presenting a fronto-parietal abscess associated with an asymptomatic atrial septal defect. Positron emission tomography (PET) study revealed high uptake of L-[methyl-11C]methionine ([11C]methionine) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) around the brain abscess. We suggest (1) to exclude a silent cardiac malformation in the presence of a cerebral abscess of unknown source occurring in adults; (2) to consider the diagnosis of brain abscess in cases of high uptake of [11C]methionine and FDG in relation to a brain lesion.

Effects of the oral form of ondansetron on cerebellar dysfunction: a multi-center double-blind study

Abstract. The aim of this study was to assess the efficacy and the safety of ondansetron administered orally in patients with a cerebellar disorder. The study was a randomised, multi-center, double-blind trial. The patients were randomised either to oral ondansetron 8 mg or to placebo twice daily for seven days. Cerebellar dysfunction was quantified before and after treatment using the International Cooperative Ataxia Rating Scale (ICARS). We performed a global analysis (total scores), we analysed by subscores (4 subscores: oculomotor, speech, kinetic, postural) and subgroups (4 subgroups: Cerebellar Cortical Atrophy (CCA), Multiple Systemic Atrophy (MSA), Familial Cerebellar Degeneration (FCD) and miscellaneous cerebellar disorders), and we also performed an analysis by individual test items. We investigated whether ondansetron and placebo had different effects upon ICARS total scores and subscores in the 4 subgroups considered together or separately. For p values < 0.05, we subsequently applied the Mann-Whitney test to compare ondansetron and placebo effect for each individual item. We evaluated 45 of the 46 patients included. No effect was found in global analysis. We found no difference in the analysis of the ICARS subscores. Concerning the individual test items, there was a significant difference between the placebo and ondansetron for the finger-to-nose test (p = 0.049), the Heel-to-Knee test (HK); (p = 0.03), the Body Sway Eyes Closed (p = 0.017) and the Body Sway Eyes Open (BSEO); (p = 0.014). There was no significant difference for tremor in upper limbs (p = 0.32) or for gait (p = 0.49). The Mann-Whitney test showed a greater effect of ondansetron than placebo for BSEO in miscellaneous disorders (p = 0.013) and for HK in FCD (p = 0.036), but ondansetron was deleterious for HK in CCA (p = 0.019). Our study showed no effect of oral ondansetron on global cerebellar dysfunction. The analysis by subgroups showed that the oral form of ondansetron (a) is deleterious for coordination in patients with CCA, (b) has no effect upon tremor in upper limbs, and (c) has a mild effect upon posture and coordination in lower limbs in some subgroups of ataxic diseases.

Effect of catechol-O-methyl transferase inhibition on peripheral and central metabolism of 6-[18F]fluoro-L-DOPA

In the presence of carbidopa, L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]fluoro-DOPA) is mainly metabolized by catechol-O-methyl transferase. We studied the effects of entacapone, a peripheral catechol-O-methyl transferase inhibitor, on striatal [18F]fluoro-DOPA uptake in rats. Rats were pretreated with carbidopa, entacapone or both before high specific activity (> 2 Ci/mmol) [18F]fluoro-DOPA administration. Entacapone alone antagonized the appearance of methylated metabolites in plasma, striatum and cerebellum but did not increase striatal [18F]fluoro-DOPA availability. Entacapone added to carbidopa significantly increased the striatum/cerebellum total radioactivity ratio (1.4 versus 1.2 in rats with carbidopa, 1.0 in controls) but significant levels of methylated metabolites were found in the brain. Entacapone added to carbidopa might increase the striatum/cerebellum total radioactivity ratio in humans undergoing [18F]fluoro-DOPA positron emission tomography (PET) studies. However, the appearance of methylated metabolites in the brain could hamper quantification of the PET data.

Effect of pergolide on endogenous and exogenous L-DOPA metabolism in the rat striatum: a microdialysis study.

We used a model of intrastriatal microdialysis in freely moving rats to study the effect of pergolide, a mixed D1/D2 dopamine (DA) receptor agonist with predominant D2 action in vivo, on the biotransformation of endogenous and exogenous L-DOPA. Levels of L-DOPA, DA, DOPAC, HVA and 5-HIAA were measured by high performance liquid chromatography. Pergolide (50 μg/kg, i.p.) caused a 47%, 65% and 70% decrease in basal striatal extracellular (EC) levels of DOPAC, HVA and DA, respectively. L-DOPA (100 mg/kg, i.p.), injected 2 hours after carbidopa, produced significant increase in EC levels of L-DOPA, DOPAC, HVA and DA in rats with and without local perfusion of 10-4 M pergolide. The DOPAC peak value was lower and was reached 60 minutes later in the group with pergolide. This study demonstrated inhibitory effects of pergolide on endogenous DA release and influence of pergolide on exogenous L-DOPA biotransformation.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

OBJECTIVE In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.

Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat.

Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission.

Basal ganglia and frontal lobe glucose metabolism. A reproducibility positron emission tomography study.

Positron emission tomography (PET) with 18F‐fluoro‐2‐deoxy‐Dglucose (FDG) is frequently used to study the metabolic correlates of movement and mental disorders. These studies generally focus on changes in the frontal cortex and the basal ganglia. The reproducibility of glucose metabolism estimates in these structures was tested in 13 normal subjects studied at rest usmg a standard and simple protocol. A reproducible dorsoventral metabolic gradient was demonstrated in the frontal cortex. Such a grad1ent was not present in the basal ganglia when the upper region of interest in the caudate nucleus, where the lower metabolic rate of glucose was probably attnbutable to partial volume effects, was not considered. Absolute values of glucose metabolic rates varied by 6.4 to 12.5% m the frontal cortex and by 6.8 to 14.7% in the basal ganglia. Vamtions in normalized values in the basal gangl1a ranged from 4.0 to 8.6%. The number of subjects required to detect statistical differences in group companson or in test‐retest studies was calculated for different anticipated levels of change. With the variability detected in this expenment, less than 10 subjects were expected to be sufficient to detect a 15% change in most regions and in both types of studies.

Pergolide potentiates L-DOPA-induced dopamine release in rat striatum after lesioning with 6-hydroxydopamine.

Summary. We used intrastriatal microdialysis to study the effect of pergolide, a D1/D2 dopamine (DA) receptor agonist on biotransformation of exogenous L-DOPA in hemi-Parkinsonian rats.DA and metabolites were assayed by microbore liquid chromatography. Pergolide (50 μg/kg, i.p) caused a 67% and 87% decrease in striatal EC levels of DA in intact and denervated striatum respectively. In intact striatum but not in denervated striatum, pergolide decreased EC levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (53% and 42% decrease, respectively). L-DOPA (100 mg/kg, i.p.) produced significant increase in EC levels of DA, DOPAC and HVA in intact and denervated striatum with and without local perfusion of 10−4 M pergolide. In denervated striatum, L-DOPA-induced DA increase was significantly higher in rats with pergolide. Our results suggest that, in an animal model of Parkinsons disease, pergolide in association with L-DOPA favors the restoration of striatal EC DA levels.

FP-CIT SPECT in clinically inconclusive Parkinsonian syndrome during amiodarone treatment: a study with follow-up.

ObjectivesTo evaluate whether dopamine transport system imaging by FP-CIT single-photon emission computed tomography (SPECT) can be helpful to differentiate idiopathic Parkinsons disease (IPD) from secondary Parkinsonism induced by amiodarone. MethodsTwenty-two patients with Parkinsonism during amiodarone therapy were evaluated by clinical neurological examination and FP-CIT SPECT. Thereafter, amiodarone was discontinued whenever possible and antiparkinsonian treatment was modified, if required. Clinical neurological status was reevaluated within a year of the SPECT examination. ResultsAt baseline, clinical neurological examination was quite similar in all patients. No clinical symptom was able to clearly orientate the diagnosis toward IPD or drug-induced Parkinsonism. Using SPECT, the number of normal and abnormal patients was evenly distributed. In the abnormal SPECT group, amiodarone was modified in seven patients of whom six improved at follow-up. Antiparkinsonian treatment had been modified in all the patients. In the four cases with no amiodarone changes, clinical improvement was noted if antiparkinsonian treatment was optimized (three patients). In the 11 normal SPECT patients, amiodarone was modified in five patients. All patients ameliorated (two) or even normalized (three). In the six patients with normal SPECT in whom amiodarone had not been modified, symptoms remained stable despite the absence of antiparkinsonian treatment. ConclusionIn patients treated with amiodarone, IPD is sometimes clinically difficult to differentiate from drug-induced Parkinsonism. Using FP-CIT, a normal scan suggests drug-induced Parkinsonism, hence, there is no need for antiparkinsonian treatment and all possible attempts to reduce or preferably stop amiodarone. An abnormal scan, on the other hand, indicates IPD. In this case, treating IPD seems to have more impact on motor changes than modifying the antiarrhythmic drug.

Systemic and intrastriatal theophylline have opposite effects on dopamine and dopamine metabolites measured by intrastriatal microdialysis in the rat

Using a model of intrastriatal microdialysis, we studied the effect of theophylline, an A1 and A2A adenosine receptor antagonist on striatal dopamine (DA) and DA metabolites. Systemic administration of theophylline (10 and 50 mg/kg) significantly reduced striatal extracellular (EC) levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy-phenylacetic acid (HVA). Intrastriatal administration of theophylline (10(-2) M) significantly increased DA and its metabolites (DA1 + 120%; DOPAC, +28%; HVA, +30%). Contradictory effects of systemic and intrastriatal theophylline point to theophylline interactions with different receptors possibly at different locations.