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It has become increasingly evident over the last years that Parkinson's disease is a multicentric neurodegenerative disease that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. The aims of the present article are to discuss the role of the enteric nervous system lesions in pathology spreading (Braak's hypothesis) and in the gastrointestinal dysfunction encountered in Parkinson's disease. Owing to its accessibility to biopsies, we further discuss the use of the enteric nervous system as an original source of biomarker in Parkinson's disease., (Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Lewy body dementia and Parkinson disease dementia are frequent causes of degenerative dementia: 20% of the dementias in patients older than 65 years are caused by the former and nearly 80% of patients with advanced Parkinson disease develop the latter. Symptoms of Lewy body dementia include fluctuations of cognitive performance, frontal and visuospatial impairment, visual hallucinations, and parkinsonism. Parkinson disease dementia could be differentiated in two subtypes: a "subcortical" subtype, characterized by frontal impairment with apathy and dullness and a "cortical" subtype with symptoms similar to those of Lewy body dementia. Mastery of potential iatrogenic factors is important: psychotropic drugs must be prescribed at the strict minimum, and L-dopa monotherapy at the minimal dose acceptable for correcting Parkinsonian motor symptoms should be the rule. Acetylcholinesterase inhibitors may be useful in both these types of dementia: rivastigmine is approved for treating Parkinson disease dementia and clozapine for reducing hallucinations.

Toxocariasis is usually responsible for visceral larva migrans syndroms. Nervous system involvement is a rare complication. In this report, we describe one case of meningoencephalitis due to Toxocara canis in a 73-year-old man presenting with mental confusion. The diagnosis of cerebral toxocariasis was confirmed by immunodiagnosis in both serum and cerebro-spinal fluid. Cerebral toxocariasis may be suspected in patients presenting with some neurological patterns including: confusion, meningitis, meningo-encephalitis, meningo-myelitis, when the etiological assessment remains negative and the environmental context is favourable. Finding evidence of specific antibodies in both cerebro spinal fluid and serum is mandatory for the diagnosis. The main clinical features concerning cerebral toxocariasis, diagnostic tools, and therapeutic measures are discussed.

The treatment of Parkinson's disease (PD) in subjects over 70 years old is simpler than in younger subjects for correcting the consequences of dopamine deficiency, but more complex with regard to symptoms resulting from non-dopaminergic lesions (axial symptoms, cognitive decline). Due to the lower risk of occurrence of motor fluctuations and severe dyskinesia, L-DOPA is the dopaminergic treatment with the best ratio of efficacy to side effects, and can be used without reservation. Treatment of non-dopaminergic symptoms is still disappointing. Apart from a partial beneficial effect of functional rehabilitation programmes, no treatment was demonstrated to be really effective for correcting dysarthria, swallowing disorders or impairment of gait and balance. Some efficacy in reducing the cognitive deficit in PD has been recently shown by cholinergic drugs, but their functional efficacy and their mid-term impact remain poor. Analysis of the different factors involved in the genesis of symptoms in PD (with the putative interest of the use of L-DOPA as a 'diagnostic tool'), and of the comorbidity usually enables cautious and pragmatic solutions to be found.

Introduction: Idiopathic Acute Transverse Myelitis (ATM) is an inflammatory and immune-mediated disorder, distinct from infectious ATM, ATM of systemic lupus erythematosus or Sjögren's syndrome, and medullary manifestation of multiple sclerosis. Prognosis is not well-known., Objective: To evaluate clinical, paraclinical and pronognosis data in patients selected with new diagnosis criteria, classically described in idiopathic ATM., Methods: Seventeen patients with diagnosis criteria were retrospectively (1996-2005) studied. A telephone investigation was conducted in 2005 to obtained data on the clinical course., Results: Seven men and 10 women, ranging in age from 15 to 75 years (mean: 39.8 years) met these new criteria. Our study showed that epidemiological and clinical findings as well as laboratory results were in agreement with those presented in the literature. Conversely, prognosis was better since 76p.cent of the patients could walk without assistance. The clinical presentation of some of our patients and/or their progression towards other multifocal inflammatory disorders, suggests there might be links between ATM, neuromyelitis optica (NMO) and Acute Dissemined Encephalomyelitis (ADEM)., Conclusion: Patients with idiopathic ATM, selected with new criteria, have a rather good prognosis. ATM seems to be part of a continuum of neuroimmunologic disorders including NMO or ADEM although reasons explaining distinct focal disorders remain unclear.

Background: Although cannabis has been used as a medicine for several centuries, the therapeutic properties of cannabis preparations (essentially haschich and marijuana) make them far most popular as a recreational drugs., State of the Art: Scientific studies on the effects of cannabis were advanced considerably by the identification in 1964 of cannabinoid D9-tetrahydrocannadinol (THC), recognized as the major active constituent of cannabis. Cloning of the centrally located CB1 receptor in 1990 and the identification of the first endogenous ligand of the CB1 receptor, anandamide, in 1992 further advanced our knowledge., Perspective and Conclusions: Progress has incited further research on the biochemistry and pharmacology of the cannabinoids in numerous diseases of the central nervous system. In the laboratory animal, cannabinoids have demonstrated potential in motion disorders, demyelinizing disease, epilepsy, and as anti-tumor and neuroprotector agents. Several clinical studies are currently in progress, but therapeutic use of cannabinoids in humans couls be hindered by undesirable effects, particularly psychotropic effects. CB1 receptor antagonists also have interesting therapeutic potential.

Unlabelled: AN ALTERNATIVE TO SUBSTITUTE THERAPY: For more than ten years, there has been renewed interest in the surgical treatment of Parkinson's disease; notably in the stimulation of the sub-thalamic nucleus (STN)., Indications: Subthalamic neurostimulation is suitable for patients severely disabled by idiopathic Parkinson's disease despite optimal medical treatment, but sensitive to L-dopa, without cognitive or psychiatric disorders and axial symptoms., In Practice: The strict respect of the selection criteria and accurate electrode placement lead to major improvement in the Parkinsonian symptoms and the patients' quality of life. There is, however, a risk of postoperative complications, notably psychiatric which may require referral to a specialist.

Handipark, a new score for measuring the impact of Parkinson's disease on daily life activities is presented. The global score ranging from 1 to 10 (without half points) is easy to determine. For a given patient, the score takes into account 5 items describing the global impact of the disease;Inter- and intra-observer reproducibility were determined. The reliability of the score was tested during two sessions separated by a 3-week interval. Five qualified neurologists scored 30 Parkinson's patients presented randomly for scoring using a semi-structured video-recorded interview. Intra-observer reproducibility was good (concordance coefficient; k=0.74, Spearman's correlation coefficient; r=0.88). Inter-observer reproducibility was also good: r=0.96 (first session), r=0.87 (second session); the agreement coefficient between the 5 observers was k=0.85 (first session), k=0.82 (second session). Distribution curves of the Hanipark score was described in 150 Parkinson's disease patients to study the correlation with items of other scales specific for Parkinson's disease (UPDRS, Hoehn & Yahr). A number significant correlations were found. Handipark is a reliable tool easy to use in clinical practice by a large panel of physicians caring for Parkinson's disease patients to assess the impact of Parkinson's disease. Further studies are needed to assess its usefulness for the follow-up of patients and assess the therapeutic impact.

Between 1993 and 2001, we observed fifteen patients (ten men and five women, mean age 63 years) with frontotemporal dementia (FTD) which preceded signs of amyotrophic lateral sclerosis (ALS) which developed 21 months later. Mean disease duration in the fourteen deceased patients was 38 months. FTD associated with ALS is characterized by rapid course, predominance of disinhibited forms (orbito-basal), presence of aphasia with neologisms, and semantic memory disorders. Performed in all patients, single-photon emission computed tomography demonstrated a bifrontal pattern of low uptake, sometimes associated with low uptake in the anterior temporal region. In one patient, neuropathology revealed neuron atrophy and loss in the frontotemporal region, the anterior horns, and the hypoglossal nucleus. Ubiquitin-positive inclusions were visible in the dentate gyrus of the hippocampus and in the anterior horns. The dementia/ALS association is classically described is uncommon. It belongs to the FTD group since the Lund and Manchester consensus. Approximately 15 p.100 of patient with FTD can be expected to develop ALS. About 250 cases have been reported in the literature, half of them in the Pacific area where the incidence of ALS is high (55/100,000 inhabitants versus 1/100,000 in the rest of the world). Intermediary forms of FTD, semantic dementia, and progressive non-fluent aphasia are discussed since several cases of non-fluent progressive aphasia associated with ALS are reported in the literature. The links between these two degenerative diseases are discussed.

Transplantation of fetal neural cells represents an attractive replacement strategy for the treatment of certain neurodegenerative diseases. This is the case with Parkinson's disease, which results from a selective loss of dopaminergic neurons of the substantia nigra. Experimentation with animal models has demonstrated the feasibility of this approach. Grafting studies in patients have shown that intrastriatal implantation of solid grafts or cells obtained from human fetal mesencephalon usually results in a clinical benefit in patients. Despite continuous methodological progress, transplantation requires both conceptual and technical improvements. Current research aims at preventing the extensive death of donor dopaminergic neurons during the grafting procedure. However, the possibility of new sources of cells is currently being investigated. These include xenogeneic porcine neurons, or human cells programmed to produce dopamine or neurotrophic factors. A promising approach is based on the use of pluripotent stem cells derived from the brain, the bone marrow or early embryos. It is hoped that it will be possible to tightly control their proliferation and differentiation into dopaminergic neurons. Hence, it seems possible that transplantation will be widely used in the clinic in the future.

Fluctuations in the efficacy of dopaminergic treatment are defined as the intermittent recurrence of parkinsonian features during the day. After a disease duration of 5 years, over 50 p. 100 of patients already experience this complication, due both to disease progression and the treatment itself. We are now starting to understand the mechanisms responsible for fluctuations: while pharmacokinetic alterations of dopamine in the brain (i.e. a reduction in dopamine storage capacity) are clearly involved, there are also complex postsynaptic anomalies, affecting all the basal ganglia circuity. A careful semiologic analysis will help to establish the precise chronology of the fluctuations and their position with respect to drug intake. This is an essential step before any attempt is made to correct them.

Although myasthenia gravis (MG) has frequently been associated with other autoimmune disorders, it has only rarely been reported in conjunction with diseases of the nervous system. A 74-year-old patient with hypertension suddenly presented left unilateral ptosis and mastication disorders. Clinical examination showed a concomitant loss of strength distally and reduced deep tendon reflex. Electrophysiologic data indicated a diagnosis of MG and chronic inflammatory demyelinating polyneuropathy; acetylcholine receptor antibody was elevated at 4.1 nmol/L (normal < 2 nmol/L). Improvement was rapid after initiation of pyridostigmine in association with corticosteroid (1 mg/kg/day). One month later, the cranial nerve deficit disappeared and strength was normal. It is likely that a basic abnormality of immune regulation was responsible for the emergence of diseases with different clinical presentations, but similar immunopathogenesis. Corticosteroid seemed to be the most effective treatment.

Fluctuations in the efficacy of dopaminergic treatment are defined as the intermittent recurrence of parkinsonian features during the day. After a disease duration of 5 years, over 50 p. 100 of patients already experience this complication, due both to disease progression and the treatment itself. We are now starting to understand the mechanisms responsible for fluctuations: while pharmacokinetic alterations of dopamine in the brain (i.e. a reduction in dopamine storage capacity) are clearly involved, there are also complex postsynaptic anomalies, affecting all the basal ganglia circuitry. A careful semiologic analysis will help to establish the precise chronology of the fluctuations and their position with respect to drug intake. This is an essential step before any attempt is made to correct them.

L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias.

The identity of the neuronal populations (dopaminergic, noradrenergic, serotoninergic, cholinergic) that die in Parkinson's disease is well established. The cause of this degeneration, and the mechanism by which it takes place is still unknown, although there is data, at least for the dopaminergic neurons, suggesting that oxidative stress might play a role. In addition, recent ultrastructural studies of dopaminergic neurons in patients with Parkinson's disease have shown that these neurons die by apoptosis, and immunocytochemical studies have shown that the cytokine TNF-alpha, observed in microglial cells in the substantia nigra of patients post-mortem, might play a role, as might the transcription factor NF-kappa B, which is translocated into the nucleus of dopaminergic neurons in patients, a sign of its activation. We have developed an in vitro model of dopaminergic cell death that accounts for these observations. In both differentiated PC12 cells and primary cultures of mesencephalic neurons, we have shown that when the sphingomyelin-dependent signaling pathway is activated, these cells die by apoptosis, preceded by the production of superoxide radicals in the mitochondria and the nuclear translocation of NF-kappa B. TNF-alpha is known to induce all three such events: apoptosis, activation of the sphingomyelin pathway, free radical production. Our results suggest that the superoxide radicals are used as signalling molecules within the sphingomyelin pathway. These observations may help to explain the origin of the evidence, in postmortem brain from parkinsonian patients, for oxidative stress, hypothesized to be an etiological factor in this disease.