[Treatment of Parkinson's disease]. / La maladie de Parkinson : actualités thérapeutiques.

Parkinson's disease in a neurodegenerative disorder that affects as many as 1-2 % of persons aged 60 years and older. Parkinson's disease occurs infrequently under 40 years of age, with major genetic implication. Alpha-synuclein plays significant pathogenic role in Parkinson's disease. Therapeutic advances based on a synucleinrelated mechanism are now developed : immunotherapy against alpha-synuclein for example. The diagnosis of Parkinson's disease remains mostly clinical. DatScan® may be helpful to distinguish parkinsonian syndrome and essential tremor. Current therapy is mainly based on a dopamine replacement strategy using the precursor levodopa (L-Dopa) and dopamine receptor agonists. Parkinson's is also associated with non-motor symptoms like sleep disorders, autonomic symptoms, neuropsychiatric symptoms. Advanced disease is associated with emergence of feature such as freezing, falling and neuropsychological dysfunction. Nonpharmacologic treatments like exercise are fundamental elements of patients' management. Motor complications and dyskinesia are common in advanced Parkinson's disease. Continuous administration of L-Dopa/carbidopa infusion in the jejunum provides more continuous dopaminergic drug delivery and stimulation and reduce motor complications. Further other approach are developped like surgical procedures: ex : high frequency stimulation of subthalamic nucleus, the more rational target for stimulation in Parkinson's disease.

La maladie de Parkinson est une affection neurodégénérative complexe affectant 1-2 % des personnes âgées de 60 ans et plus. Des formes précoces le plus souvent d'origine génétique, existent également. Le diagnostic est basé essentiellement sur des critères cliniques et plus récemment scintigraphiques. Le DatScan® permet d'aider au diagnostic différentiel entre tremblement essentiel et syndrome parkinsonien. Grâce aux avancées de la neuro-génétique, la compréhension de l'étiologie de la maladie a progressé. L'implication de l'alpha-synucléine dans la pathogenèse de l'affection permet d'envisager de nouvelles stratégies thérapeutiques comme l'immunothérapie. Les symptômes moteurs cardinaux résultent d'une altération des circuits moteurs secondaire à la dénervation dopaminergique. La maladie de Parkinson se caractérise aussi par la présence d'une série de symptômes non moteurs comme les troubles du sommeil, les troubles autonomes, les troubles neuropsychologiques. La prise en charge multidisciplinaire est donc primordiale. Le traitement médicamenteux est essentiellement basé sur la stimulation du système dopaminergique soit en utilisant le précurseur de la dopamine, la levodopa (L-Dopa) soit par stimulation des récepteurs dopaminergiques (agonistes dopaminergiques) soit par action enzymatique ou autre… Dans les formes avancées de la maladie de Parkinson les complications motrices et les dyskinésies rendent le traitement difficile. Des stratégies plus lourdes comme la chirurgie (stimulation à haute fréquence des noyaux sous thalamiques par exemple) ou des techniques de stimulation dopaminergique continue (pompe à L-Dopa, à apomorphine) doivent être envisagées.

Depression, anxiety and non-motor symptoms on initiation of intrajejunal levodopa/carbidopa therapy.

In Parkinson's disease (PD), clinical observations and some studies suggest that depression and anxiety are linked to motor fluctuations. We studied prospectively 10 patients with advanced PD just before initiation of intrajejunal levodopa/carbidopa therapy, and after 1 and 3 months of regular treatment. Motor symptoms, motor fluctuations, non-motor symptoms, quality of sleep, symptoms of depression and anxiety were evaluated with the appropriate scales. As expected, motor symptoms and motor fluctuations improved considerably. Non-motor symptoms, quality of sleep and depression also improved significantly. However, anxiety score remained unchanged during the study. Our data in a small numbers of patients indicate that all aspects of mental and psychic symptoms are not alleviated within a short period of reduction of motor fluctuations.

[1231-FP-CIT (DaTSCAN) scintigraphy in the differential diagnosis of movement disorders]. / Apport de la scintigraphie par 123I-fP-CIT (DaTSCAN) au diagnostic différentiel des troubles du mouvement.

The diagnosis of idiopathic Parkinson's disease (IPD) remains mostly clinical. Nevertheless, differentiating IPD from essential tremor or other parkinsonian syndromes solely by clinical examination can be challenging in some cases, especially in the early stage of the disease. The introduction of new isotopic functional imaging techniques, and more specifically the labelling of dopamine transporter derivatives, has improved the understanding and early detection of some diseases affecting the basal ganglia. Iodine-123-FP-CIT (DaTSCAN), a (presynaptic) dopamine transporter analogue for nuclear medicine imaging, has recently been introduced for the non-invasive differential diagnosis between IPD and essential tremor or secondary (e.g. drug-related) parkinsonian syndromes. DaTSCAN scintigraphy has also demonstrated some usefulness in the evaluation of other neurodegenerative parkinsonian syndromes such as Lewy-body dementia or multiple system atrophy. For this latter however, the DaTSCAN has to be combined with a second scintigraphy, imaging the post-synaptic dopaminergic receptors, such as the D2-ligand 123I-iodobenzamide. Combining DaTSCAN scintigraphy to a functional study of the brain cortical activity using a brain perfusion scintigraphy or to the evaluation of the cardiac adrenergic system by means of a myocardial MIBG scintigraphy (a norepinephrine storage analogue) can also be helpful to refine the diagnosis. Our experience shows that a good collaboration between the neurologist specialized in movement disorders and the nuclear medicine physician is useful, if not mandatory, to optimize the diagnostic performances of DaTSCAN scintigraphy.

Effects of the oral form of ondansetron on cerebellar dysfunction. A multi-center double-blind study.

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.

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

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 micrograms/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 Parkinson's disease, pergolide in association with L-DOPA favors the restoration of striatal EC DA levels.

[Lesions of ponto-cerebellar and olivo-cerebellar afferents demonstrated by neurophysiologic analysis]. / Atteinte des afférences ponto-cérébelleuses et olivo-cérébelleuses mise en évidence par l'analyse neurophysiologique.

We describe a 52-year-old woman presenting a 2-year history of limb clumsiness and gait difficulties, characterized by progressive worsening. Neurological examination revealed cerebellar intention tremor, cerebellar dysmetria of all 4 limbs and ataxic gait. However, brain MRI was normal. Analysis of fast wrist flexion movements demonstrated hypometric movements, with decreased intensities of agonist EMG activities and increased durations of antagonist EMG activities. Such EMG abnormalities have been demonstrated in patients presenting lesions of the middle cerebellar peduncle, affecting the crossed cerebellopontine projections. Moreover, adaptation motor learning during a pinch task (isometric force) showed a severe inability to adapt motor programming, indicating a disruption of cerebellolivary and cerebellopontine afferent systems. We suggest that our patient presented an exceptional brainstem syndrome involving the function of cerebellar inflow tracts. Such electrophysiological findings are not encountered in patients presenting a cerebellar cortical degeneration or cerebellovlivopontine atrophy, and might have important implications in the treatment of cerebellar ataxia in the future.

Asymmetry of basal ganglia glucose metabolism and dopa responsiveness in parkinsonism.

We investigated, by positron emission tomography (PET) with [18F]fluoro-2-deoxy-d-glucose (FDG) (FDG-PET), brain glucose metabolism in 19 patients with parkinsonian features. We compared local pattern of FDG uptake and asymmetry indexes in patients with therapeutic response to levodopa (L-dopa) (group 1, presumed Parkinson's disease, n = 9) and patients without L-dopa therapeutic response (group 2, presumed striatonigral degeneration, n = 10). Limb dystonia was present in 11% of patients in group 1 and in 40% of patients in group 2. Asymmetry in basal ganglia metabolism was distributed differently in the two groups (analysis of variance, p < 0.04). In superior and inferior putamen, superior and middle caudate, ventral striatum, and inferior thalamus, relative reduction in metabolism on the side contralateral to predominant parkinsonian signs was associated with L-dopa unresponsiveness. On the contrary, in middle caudate, ventral striatum, and inferior thalamus, a relative increase in metabolism on the side contralateral to the predominant side, parkinsonian signs were found in L-dopa-responsive patients. Our FDG-PET study using simple statistical procedures demonstrates inverse asymmetry of basal ganglia glucose metabolism in parkinsonian patients grouped on the sole basis of L-dopa responsiveness.

Regional methionine and glucose uptake in high-grade gliomas: a comparative study on PET-guided stereotactic biopsy.

UNLABELLED: Gliomas are regionally heterogeneous tumors. The local relationship between histologic features and radiotracer uptake evaluated by PET should therefore influence analysis and interpretation of PET results on gliomas. This study explored this local relationship as a result of PET guidance of stereotactic biopsies. METHODS: Local histology was confronted to the regional uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and 11C-methionine (11C-MET) in 14 patients with high-grade glioma diagnosed during a procedure of PET-guided stereotactic biopsies. We analyzed the uptake of both tracers in regions of interest centered on the stereotactic coordinates of 93 biopsy samples. RESULTS: A semiquantitative analysis revealed a significant regional correlation between 11C-MET and 18F-FDG uptakes. Uptake of both tracers was significantly higher on the site of tumor samples showing anaplastic changes than in the rest of the tumor. Presence of necrosis in anaplastic areas of the tumor significantly reduced the uptake of 11C-MET. CONCLUSION: PET with 11C-MET and 18F-FDG may help to evaluate, in vivo, the metabolic heterogeneity of human gliomas. Anaplasia is a factor of increased uptake of both tracers, but microscopic necrosis in anaplastic areas influences their uptake differently. This finding probably relates to the differences in tracer uptake by non-neoplastic components of necrotic tumors. These results underline the complementary role of 18F-FDG and 11C-MET for the study of brain tumors and favors their use for stereotactic PET guidance of diagnostic or therapeutic procedures.

Microdialysis-HPLC for plasma levodopa and metabolites monitoring in parkinsonian patients.

We used in vitro microdialysis-HPLC to determine L-3,4-dihydroxyphenylalanine (L-DOPA) and its metabolites in plasma of patients with advanced Parkinson disease. Blood samples and clinical evaluations were obtained 0, 30, 60, 90, 120, and 150 min after oral administration of carbidopa/L-DOPA (25/100 mg, 12.5/125 mg, and 50/200 mg). In vitro recoveries for L-DOPA and metabolites ranged from 22% to 36%. Linear correlation was found between metabolite concentrations in the dialysate and in the surrounding medium. There was a significant positive correlation between L-DOPA dose and plasma concentration of L-DOPA and homovanillic acid (P < 0.04). Clinical response was maximum 60 min after L-DOPA administration. Threshold L-DOPA plasma concentration averaged 7.74 +/- 3.3 mumol/L. Motor effect is longer with the highest L-DOPA peak concentration (P < 0.01). Microdialysis-HPLC is readily applicable, reproducible, and allows monitoring of plasma L-DOPA and metabolites in parkinsonian patients.

In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: a film and electronic autoradiographic study.

To further validate its use in positron emission tomography (PET), we studied the binding of [18F]altanserin, a specific 5HT2 radioligand, in the rat brain using in vivo autoradiography. Distribution of [18F]altanserin binding was comparable to the in vitro mapping of 5HT2 receptors reported in the literature. Selective displacers were used to test the reversibility and the selectivity of this radioligand. Specific binding of [18F]altanserin in the rat frontal cortex was quantified by direct counting with an electronic imaging system and by quantification on digitalized autoradiograms. Close results of about 30 pmol/g were obtained with both methods. Our data confirmed that [18F]altanserin is a valid tracer for 5HT2 receptors binding studies.

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.

Intracerebral transplantation of fetal ventral mesencephalon for patients with advanced Parkinson's disease. Methodology and 6-month to 1-year follow-up in 3 patients.

In order to launch a new transplantation program for Parkinson's disease (PD), we evaluated the safety and efficacy of fetal ventral mesencephalic grafts in 3 patients with advanced PD. Inclusion criteria and clinical evaluation followed strictly the Core Assessment Program for Intracerebral Transplantation. The transplantation procedure was based on the technique previously described by the groups in Lund (Sweden) and Créteil (France). The putamen contralateral to the site of predominant symptoms was unilaterally grafted in all patients. Magnetic resonance (MR)-based stereotactic guidance with multiplanar correlation was used to define 3 implantation trajectories in the precommissural, commissural, and postcommissural putamen. Fetal ventral mesencephalon was prepared from 6- to 8-week-old human embryos obtained from same-day abortions. Under general anesthesia, 8 deposits of 3 microliters of the fetal tissue were placed 1 mm apart along each implantation trajectory using a customized microsyringe and needle attached to the stereotactic frame. The patients recovered uneventfully from the neurosurgical procedure. Early postoperative MR clearly showed the implantation trajectories reaching the putamen in all patients. The follow-up period was of 12, 9 and 6 months, for each of the 3 patients, respectively. Clinical changes appeared between 3 and 6 months after transplantation and consisted of an increase in the 'on' periods and in quantitative bilateral improvement in the motor timed tests. There was an improvement of the Unified Parkinson's Disease Rating Scale score and an improvement of rigidity. Tremor was unchanged, and there was a slight and transient increase in dyskinesias. Neuropsychological follow-up revealed slight frontal alterations in 2 patients. Positron emission tomography demonstrated an increase of 18F-fluorodopa uptake in the grafted site. Adverse events include a reversible Cushing syndrome secondary to immunosuppression in 1 patient and a transient episode of confusion in another. The results of this study, designed as a prerequisite for a wider transplantation program, are in accordance with those previously reported by others and show that, using standardized neurosurgical techniques and methods of evaluation, transplantation is a reproducible and safe therapeutic approach which provides clinical benefits to patients with advanced PD.

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.

Slow increase of homovanillic acid in cerebrospinal fluid after levodopa administration.

Concentrations of major catabolites of dopamine were followed in the ventricular cerebrospinal fluid (CSF) in five patients undergoing intracranial pressure monitoring for chronic hydrocephalus. Determinations were made every 2 h following the administration of carbidopa/levodopa 25/250 mg (one Sinemet capsule) given 8 h apart. The rise of homovanillic acid (HVA) concentrations was slow and progressive, reaching the level of statistical significance (p < or = 0.01) only 8 h after the second administration of Sinemet. The rise in 3,4-dihydroxyphenylacetic acid (DOPAC) was faster than the rise in HVA, with the peak value detected 4 h after the first administration of Sinemet. These data are interpreted as a confirmation, in humans, of a slow pool of exogenous levodopa, previously demonstrated in animal studies.

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.

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

Positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (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 using a standard and simple protocol. A reproducible dorsoventral metabolic gradient was demonstrated in the frontal cortex. Such a gradient 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 attributable to partial volume effects, was not considered. Absolute values of glucose metabolic rates varied by 6.4 to 12.5% in the frontal cortex and by 6.8 to 14.7% in the basal ganglia. Variations in normalized values in the basal ganglia ranged from 4.0 to 8.6%. The number of subjects required to detect statistical differences in group comparison or in test-retest studies was calculated for different anticipated levels of change. With the variability detected in this experiment, less than 10 subjects were expected to be sufficient to detect a 15% change in most regions and in both types of studies.

History of brain and epidural metastases from breast cancer in relation with the disease evolution outside the central nervous system.

We reviewed 89 breast cancer patients with brain or epidural metastases in order to see whether a parallelism could be found between disease evolution inside and outside the central nervous system. One-fifth of the patients with brain metastases did not have any other site of relapse before neurological complication. Among the 38 patients who developed brain metastases and had a prior history of relapse outside the brain, 12 had control of constant extracranial sites while disease was progressing at these sites in 26 of them. In the epidural metastases group, all patients but 4 had progressive disease elsewhere when neurological complication appeared.

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 micrograms/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.

Carbon-11-methionine and fluorine-18-FDG PET study in brain hematoma.

Three patients were examined using PET with L-methyl-11C-methionine (11C-methionine) and 2-18F-fluoro-2-deoxy-D-glucose (FDG) 20 to 32 days after the occurrence of nontumoral brain hematomas. PET revealed high uptake of 11C-methionine in the area surrounding the hematoma in all three patients. In two patients, discrete spots of moderate uptake of FDG were found at the periphery of a hypometabolic area. PET studies were repeated in two patients 76 and 103 days after the bleeding, respectively, and showed a dramatic decrease in 11C-methionine uptake around the hematoma. The spots of FDG uptake disappeared on the repeated late scans. We hypothesize that the subacute gliotic reaction surrounding brain hematomas is responsible for increased uptake of 11C-methionine and for the presence of spots of FDG uptake. PET studies with 11C-methionine and FDG performed 20 to 32 days after the initial symptom are not helpful in the differentiation between neoplastic and non-neoplastic origins of an intracerebral hemorrhage since tracer uptake at the periphery of the lesion may be increased in both.