Deep brain pallidal stimulation for movement disorders in neuroacanthocytosis.
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Acanthocytes↗
Biomedical subjects
I Ghorayeb
Publications and source records attributed to I Ghorayeb.
The restless legs syndrome.
The restless legs syndrome (RLS) is one of the commonest neurological sensorimotor disorders at least in the Western countries and is often associated with periodic limb movements (PLM) during sleep leading to severe insomnia. However, it remains largely underdiagnosed and its underlying pathogenesis is presently unknown. Women are more affected than men and early-onset disease is associated with familial cases. A genetic origin has been suggested but the mode of inheritance is unknown. Secondary causes of RLS may share a common underlying pathophysiology implicating iron deficiency or misuse. The excellent response to dopaminegic drugs points to a central role of dopamine in the pathophysiology of RLS. Iron may also represent a primary factor in the development of RLS, as suggested by recent pathological and brain imaging studies. However, the way dopamine and iron, and probably other compounds, interact to generate the circadian pattern in the occurrence of RLS and PLM symptoms remains unknown. The same is also the case for the level of interaction of the two compounds within the central nervous system (CNS). Recent electrophysiological and animals studies suggest that complex spinal mechanisms are involved in the generation of RLS and PLM symptomatology. Dopamine modulation of spinal reflexes through dopamine D3 receptors was recently highlighted in animal models. The present review suggests that RLS is a complex disorder that may result from a complex dysfunction of interacting neuronal networks at one or several levels of the CNS and involving numerous neurotransmitter systems.
Animals↗
Sleep disorders in multiple system atrophy.
Complaints about sleep disorders and excessive daytime sleepiness are common among patients with multiple system atrophy. The diffuse neurodegenerative process that encompasses the key structures involved in the regulation of the sleep/wake transition and respiratory function may account for these complaints and for the most frequent polysomnographic findings in MSA, i.e., sleep-related breathing disturbances and REM sleep behaviour disorder, which are both treatable conditions. Nocturnal stridor is an inspiratory sound produced by complex vocal cord muscle dysfunction. Often occurring with sleep apnoea, stridor is associated with decreased survival. REM sleep behaviour disorder, a parasomnia characterized by loss of normal skeletal muscle atonia during REM sleep with prominent motor activity, is detected in almost all patients. The pathophysiology of both disorders is partially elucidated but increasing evidence points to the role of basal ganglia dysfunction.
Animals↗
The European Multiple System Atrophy-Study Group (EMSA-SG).
Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.
Animals↗
[Animal models of parkinsonism].
Research into the pathophysiology of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 6-hydroxydopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates. Their combination with specific striatal toxins, such as quinolinic acid or 3-nitropropionic acid, has led to the development of experimental models replicating the salient pathological and clinical features of multiple system atrophy of the striatonigral degeneration subtype both in rodents and primates. More recently, the identification of alpha-synuclein gene mutations in rare familial cases of Parkinson's disease has led to the development of alpha-synuclein knock-out and transgenic animals. We conclude that the use and improvement of both phenotypic and genetic models can significantly speed progress toward understanding the pathophysiology of these devastating diseases and finding innovative cures.
Animals↗
Relationship between stridor and sleep apnoea syndrome: is it as simple as that?
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Humans↗
Dystonia is predictive of subsequent altered dopaminergic responsiveness in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine+3-nitropropionic acid model of striatonigral degeneration in monkeys.
We conducted a new chronic sequential 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) intoxication paradigm in two female monkeys in order to reproduce the striatonigral degeneration type of levodopa-unresponsive parkinsonism. A comparison was made with MPTP-, 3NP-intoxicated and control monkeys. A levodopa-responsive parkinsonism emerged in all MPTP-treated monkeys. During subsequent 3NP intoxication, one of the two MPTP +3NP monkeys exhibited hindlimb dystonia concomitantly with a reduced levodopa response. All MPTP-monkeys had severe cell loss in the substantia nigra pars compacta (>70%), but 3NP-induced discrete lesioned areas and cell loss predominantly in the putamen appeared only in the dystonic and levodopa-unresponsive animal. We propose that the appearance of dystonia after 3NP intoxication following dopaminergic striatal denervation is the key symptom predictive of the loss of dopaminergic response.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
A 'single toxin-double lesion' rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis.
Previous attempts to reproduce striatonigral degeneration, the core pathology underlying Parkinsonism in multiple system atrophy, have been impeded by interactions in the neurotoxins used to replicate striatal and nigral degeneration in rodents. To overcome these interactions, we have developed a new model of striatonigral degeneration which uses a single unilateral administration of 1-methyl-4-phenylpyridinium ion (MPP(+)) into the rat striatum. Spontaneous and drug-induced rotational behaviour, thigmotactic scanning, stepping adjusting steps and paw reaching deficits were compared in four groups of animals: group 1 (control), group 2 (20 microg quinolinic acid), group 3 (20 microg 6-hydroxydopamine), and group 4 (90 nmol MPP(+)). MPP(+) administration resulted in the absence of the amphetamine-induced ipsilateral bias observed in the 6-hydroxydopamine group and of the apomorphine-induced ipsilateral bias observed in the quinolinic acid group. There was no thigmotactic scanning asymmetry in the MPP(+)-injected rats compared to the quinolinic acid- and the 6-hydroxydopamine-injected rats. MPP(+) elicited a bilateral stepping adjustment deficit similar to that found in the quinolinic acid group when compared to controls. MPP(+) also elicited a more severe and significant contralateral deficit in paw reaching compared to controls, 6-hydroxydopamine and quinolinic acid groups. Histopathology revealed a significant reduction of the lesioned striatal surface (-47.53%) with neuronal loss and increased astrogliosis in the MPP(+) group grossly similar to that found in the quinolinic acid group. Contrary to the latter group, however, loss of intrastriatal and striatal-crossing fibre bundles was observed in the MPP(+) group as there was also some retrograde degeneration in the ipsilateral thalamic parafascicular nucleus. The mean loss of dopaminergic cells in the ipsilateral substantia nigra pars compacta in MPP(+) rats was less marked (-48.8%) than in the 6-hydroxydopamine rats (-63.6%) and was not significant in quinolinic acid rats (-5.2%). This study shows that a single unilateral intrastriatal administration of MPP(+) induces a unique motor behaviour resulting from both nigral and striatal degeneration, but also from possible extrastriatal damage. This 'single toxin-double lesion' paradigm may thus serve as a rat model of striatonigral degeneration.
1-Methyl-4-phenylpyridinium↗
Sleep disorders and their determinants in multiple system atrophy.
OBJECTIVES: To evaluate the incidence, types, determinants, and consequences of sleep disorders in patients with multiple system atrophy (MSA) and determine whether their characteristics are similar to those of patients with Parkinson's disease (PD). METHODS: Information about sleep disorders was collected using a standardised questionnaire in an unselected group of 57 patients with MSA and in 62 patients with PD matched as a group for age, sex distribution, and disease duration. RESULTS: Seventy percent of patients with MSA complained of sleep disorders compared with 51% of patients with PD (p=0.03). The most commonly reported sleep disorders were sleep fragmentation (52.5%), vocalisation (60%), REM sleep behaviour disorder (47.5%), and nocturnal stridor (19%). Except for sleep fragmentation, the incidence of these disorders was significantly higher than in PD. Sleep problems tended to be associated with more severe motor symptoms, longer disease duration, depression, and longer duration of levodopa treatment. Half of patients with MSA with sleep disorders complained of daytime somnolence compared with 30% of patients with PD. Daytime somnolence was significantly associated with disease severity in MSA. CONCLUSION: This study shows that sleep disorders are more common in patients with MSA than in those with PD after the same duration of the disease, reflecting the more diffuse underlying pathological process in MSA.
Aged↗
Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration.
Animal models reproducing early stages of striatonigral degeneration (SND), the core pathology underlying parkinsonism in multiple system atrophy, are lacking. We have developed a new model of early-stage SND by using a simultaneous unilateral administration of quinolinic acid (QA) and 6-hydroxydopamine (6-OHDA) into the putaminal equivalent of the rat striatum. Spontaneous and drug-induced behavior, thigmotactic scanning, paw reaching deficits, and histopathology were studied in rat groups: group 1 (control), group 2 (QA), group 3 (6-OHDA), and group 4 (QA + 6-OHDA). The double toxin administration resulted in reduction of the spontaneous and the amphetamine-induced ipsiversive bias in the 6-OHDA group and in a reduction of the apomorphine-induced ipsiversive rotations in the QA group. Simultaneous QA and 6-OHDA also reduced the thigmotactic bias observed in the 6-OHDA rats. Combined toxin elicited a nonsignificant contralateral deficit in paw reaching but a significant deficit on the ipsilateral side. Histopathology revealed a significant reduction of the lesioned striatal surface (-27%) with neuronal loss and increased astrogliosis in group 4 compared to group 2, consistent with an exacerbation of QA toxicity by additional 6-OHDA. By contrast, the mean loss of the TH-positive neurons in the ipsilateral substantia nigra pars compacta (SNc) of group 4 was less marked (-15%) than in the 6-OHDA group (-36%), indicating a possible protective action of intrastriatal QA upon 6-OHDA retrograde SNc degeneration. This study shows that a combined unilateral intrastriatal administration of QA and 6-OHDA may serve as a model of early stage SND which is more suitable for early therapeutic interventions.
Animals↗
Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum.
The striatum is regulated by dopaminergic inputs from the substantia nigra. Several anatomical studies using in situ hybridization have demonstrated that in rodents, dopamine D1 and D2 receptors are segregated into distinct striatal efferent populations: dopamine D1 receptor into gamma-aminobutyric acid (GABA)/substance P striatonigral neurons, and dopamine D2 receptor into GABA/enkephalin striatopallidal neurons. The existence of such a segregation has not been investigated in primates. Therefore, to quantify the efferent striatal GABAergic neurons in the adult Cynomolgus monkey, we detected GAD67 mRNA expression while considering that only a minority of the GABAergic population is composed of interneurons. To characterize the peptidergic phenotype of the neurons expressing dopamine D1 or D2 receptors, we examined the mRNA coding for these receptors in the striatum at the cellular level using single- and double in situ hybridization with digoxigenin and 35S ribonucleotide probes. Double in situ hybridization demonstrated a high coexpression of dopamine D1 receptor and substance P mRNAs (91-99%) as well as dopamine D2 receptor and preproenkephalin A mRNAs (96-99%) in medium-sized neurons throughout the nucleus caudatus, putamen, and nucleus accumbens. Only a small subpopulation (2-5%) of the neurons that contained dopamine D1 receptor mRNA also expressed dopamine D2 receptor mRNA in all regions. Large-sized neurons known to be cholinergic expressed D2R mRNA. However, within the nucleus basalis of Meynert, the large cholinergic neurons expressed D2R mRNA, but the neurons producing enkephalin expressed neither D1R nor D2R mRNA. These results demonstrate that the striatal organizational pattern of D1 and D2 receptor segregation in distinct neuronal populations described in rodent also exists in primate.
Animals↗
Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration.
We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa-unresponsive parkinsonism associated with multiple systemic atrophy (MSA-P), by sequential systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) in a Macaca fascicularis monkey. L-Dopa-responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the L-dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre-pro-enkephalin A- and substance P-containing cells, whereas somatostatin (NADPH-diaphorase)-containing interneurons were relatively spared. Our model therefore reproduced levodopa-unresponsive parkinsonism and SND-like pathologic changes characteristic of MSA-P. The double-lesion primate model of SND may serve as a preclinical test-bed for the evaluation of novel therapeutic strategies in MSA-P.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy).
This study characterizes paw reaching, stepping and balance abnormalities in a double lesion rat model of striatonigral degeneration, the core pathology underlying levodopa unresponsive parkinsonism associated with multiple system atrophy. Extensive unilateral nigral or striatal lesions induced by 6-hydroxydopamine or quinolinic acid, respectively, produced a similarly marked contralateral paw reaching deficit without further deterioration following a secondary (complementary) lesion of ipsilateral striatum or substantia nigra. Contralateral stepping rates were reduced by unilateral 6-hydroxydopamine lesions without further deterioration following the secondary striatal lesion. In contrast, initial unilateral striatal quinolinic acid injections induced bilateral stepping deficits that significantly worsened contralaterally following the secondary nigral lesion. Contralateral sidefalling rates were significantly increased following primary nigral and striatal lesions. Secondary nigral but not secondary striatal lesions worsened contralateral sidefalling rates. Histological studies revealed subtotal (>90%) depletion of dopaminergic neurons in substantia nigra pars compacta and variable degrees of striatal degeneration depending on the lesion sequence. Animals pre-lesioned with 6-hydroxydopamine showed significantly larger residual striatal surface areas following the secondary striatal quinolinic acid lesion compared to animals with primary striatal quinolinic acid lesions (P<0.001). These findings are in line with previous experimental studies demonstrating that striatal dopamine depletion confers neuroprotection against subsequent excitotoxic injury. Whether loss of dopaminergic neurons protects against the striatal disease process occurring in multiple system atrophy (Parkinson-type) remains to be elucidated. In summary, this is the first experimental study to investigate spontaneous motor behaviour in a unilateral double lesion rat model. Our observations are consistent with a complex interaction of nigral and striatal lesions producing distinct behavioural and histological changes depending on the lesion sequence. Tests of forelimb akinesia and complex motor behaviour appear to provide a reliable tool that will be helpful for monitoring the effects of interventional strategies such as embryonic neuronal transplantation in the rat model of striatonigral degeneration.
Animals↗
[Occupational exposure to cadmium and renal cancer. Apropos of a case].
INTRODUCTION: Cadmium is a carcinogenic substance and bronchial and prostatic cancer may be readily identified as professional diseases. It is also a nephrotoxic substance but renal carcinoma are rarely imputed to this kind of intoxication. CASE REPORT: We report the observation of a 59-year-old woman with a long unprotected professional exposure to cadmium. She developed an epidermoid carcinoma of the kidney and later of the lung. Levels of cadmium in blood samples were abnormally high, confirming the existence of a chronic impregnation. CONCLUSION: We have judged cadmium to be responsible for her renal disease: the fact of a long unprotected professional exposure, the scarcity of renal epidermoid carcinoma, the well established nephrotoxicity of this substance and the association with other cancers, appear to us as convincing evidence, and the kidney cancer of our patient has been considered a professional disease.
Cadmium↗
Creutzfeldt-Jakob disease with long duration and panencephalopathic lesions: molecular analysis of one case.
A 49-year-old woman presented with isolated aphasia followed by dementia and ataxia with a duration of 4 years. Histopathologically there was panencephalic involvement, status spongiosus, and kuru-type plaques. Molecular analysis showed heterozygosity at codon 129 in the prion protein (PrP) gene, and type 2 protease-resistant PrP. The comparison between this case and those previously reported suggests that the panencephalopathic variant of Creutzfeldt-Jakob disease (CJD) is an aspecific end-stage condition displayed by most if not all CJD variants in individual patients with an unusually prolonged course.
Biopsy↗
Objective measurement of sleepiness in summer vacation long-distance drivers.
The study investigated whether sleepiness at the wheel is a problem in non-commercial drivers going on summer vacation. All drivers, who stopped at a rest area on a large European freeway while one of the interviewers was available, were systematically approached and asked to respond to a questionnaire. All subjects who had driven at least 400 km (240 miles), whose age was between 20 and 46 years of age, and who agreed to participate were asked to undergo a longer investigation that included a short sleep/wake diary describing overall sleep habits during the year, a sleep/wake log covering the days just prior to departure, an analog visual scale indicating sleepiness at time of interview, and a polygraphically monitored two nap sleep test (TNST). A control group was recruited that consisted of subjects of the same age range, normal sleep habits, and normal nocturnal sleep time before administration of the TNST. One hundred and four drivers (2 women) participated between 08:00 and 20:00 h. The total group was subdivided into 6 subgroups based upon the time of day of their investigation (08:00-10:00 h, 10:01-12:00 h, etc.). The control group included 50 men with 50-55% of control subjects, relative to the total number of index-cases, in each subgroup. Eighty-eight percent (n = 92) of studied drivers had experienced acute sleep deprivation within one day prior to departure due to the planned long driving. The TNST demonstrated that, overall, drivers had a significantly shorter sleep latency in nap 1 and nap 2 than controls, had a significantly longer sleep duration in nap 1 and nap 2, and there was a significant correlation between the sleep debt prior to departure and the sleep stage reached during the TNST. It is concluded that the TNST is a test which allows the objective study of sleepiness in drivers without the burden of the multiple sleep latency test. Many drivers are excessively sleepy when making long summer vacation journeys.
Adult↗
Determinants of sleepiness in automobile drivers.
Governmental agencies do not systematically investigate the presence of daytime sleepiness as a determinant of driving accidents. We surveyed automobile drivers traveling on summer vacations and driving long distances on a European highway. We evaluated their subjective daytime sleepiness while driving and any sleep deprivation just prior to departure. Five-hundred sixty-seven automobile drivers (mean age 37.7 +/- 11 years) were interviewed at a roadside rest-stop. Questions covered the sleep/wake schedule during the year, sleep habits, and the presence of symptoms frequently associated with sleep-disordered breathing. Sleep behavior just prior to departure was compared to the usual sleep schedule during the year. Fifty percent of the responders had a sleep restriction just prior to departure (mean -203 minutes) compared to usual total sleep time during the year; 10% had no nocturnal sleep prior to departure. Drivers younger than 30 years were significantly more acutely sleep deprived than other drivers. Economic migrants (subjects with low economic status) also experienced significant acute sleep restriction.
Accidents, Traffic↗
[Systemic lupus erythematosus, caused by carbamazepine. Apropos of a case].
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Adolescent↗