Olivier Blin

Quantitative analysis of gait in Parkinson patients : increased variability of stride length

Analysis of the spatio-temporal and kinematic parameters of locomotion recorded in 21 parkinsonian patients compared to 58 normal elderly subjects showed significant differences in all the recorded parameters. However the relationship between these parameters was preserved, as was the basic locomotor pattern. The variability of stride length, more marked in parkinsonian patients, increased as a function of the clinical stages of Hoehn and Yahr. This index could be useful in assessing the course of the disease in patients.

Dopa-sensitive and Dopa-resistant gait parameters in Parkinson's disease

Quantitative analysis of gait was performed in 20 parkinsonians before and 1 h after the acute administration of L-Dopa in order to discriminate between the Dopa-sensitive and the Dopa-resistant kinematic gait parameters. The stride length and the kinematic parameters (swing velocity, peak velocity) related to the energy were Dopa-sensitive. The improvement of the bent forward posture by L-Dopa may explain the stride length increase. Temporal parameters (stride and swing duration, stride duration variability), related to rhythm, were Dopa-resistant. Experimental data argue for the importance of force control in maintaining the posture. The stride length variability, possibly related to the variability of force production shown to exist in parkinsonians was not significantly improved by L-Dopa. In Parkinsons disease different hypotheses might explain the inexorable aggravation of gait disorders along the course of the disease: (1) an advancing disorder of coordination between postural control and locomotion, (2) if some gait parameters like stride length and kinematic parameters are Dopa-sensitive, the others are Dopa-resistant and thus may involve other mechanisms than dopamine deficiency.

OLANZAPINE VERSUS HALOPERIDOL : ACUTE PHASE RESULTS OF THE INTERNATIONAL DOUBLE-BLIND OLANZAPINE TRIAL

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti‐GM1 antibodies A double‐blind, placebo‐controlled study

We studied the effects of intravenous immunoglobulin (IVIg) in 12 patients with motor neuron syndromes associated with high titers of anti-GM1 antibodies. Five of the patients had conduction blocks. The study design was a double-blind, placebo-controlled, crossover trial with IVIg (0.4 g/kg body weight per day injected for 5 consecutive days). We evaluated the patients before and 5, 28, and 56 days after drug administration using a computerized analyzer for muscle strength, the Norris scale for disability, motor nerve conduction velocities for patients with conduction blocks, and measurements of immunologic markers. Compared with placebo, IVIg induced a significant increase in muscle strength only in the patients with conduction blocks.

Orphandev, French Clinical Trials Network dedicated to Orphan drugs and therapeutics development for rare diseases

Though rare diseases affect fewer patients than common diseases, developing drugs for them is subject to the same principles. But constructing and leading rare diseases clinical trials means also facing numerous difficulties which are more important in this field (methodology, little knowledge of the disease’s evolution, choice of the judgment’s criteria, small population’s size, logistical matters...) However during the last decade, France led several initiatives to improve the burden of rare diseases. Centres of Expertise were identified, ability centres have been appointed and a National Plan for rare diseases was developed. Nevertheless, in spite of the great dynamic created by France, development and availability of orphan therapeutics remain problematic regarding rare diseases specificities. In this context, it is important to gather skills and strengths to make patients benefit from fundamental research’s results and accelerate clinical trials. Orphandev is a French Clinical Trials Network based on a strong collaboration principle with all actors involved (academics, industries and patients) dedicated to orphan drugs development. It was created by academics to help academics but also others actors involved in rare diseases’ research. The Network’ skills have already been dedicated to orphan drugs’ trials: Charcot Marie Tooth (2004), Rett (2006) and Progeria (2008). Orphandev has intervened according to the mutualisation and translational research concepts from the experimental phase (in vitro and animals’ tests) to the results’ valorisation with every single actor involved in the study. With the experience gained and the successful results, we have developed an organisational concept in order to capitalise on the lessons learnt and optimise the trials process. In a time of great therapeutics development with solutions coming from gene breakthroughs but not only, Orphandev allows for further improvement of the interface between fundamental research, clinical research and drug developments in rare diseases in a more operational way.

Neural bases of different cognitive strategies for facial affect processing in schizophrenia

OBJECTIVE To examine the neural basis and dynamics of facial affect processing in schizophrenic patients as compared to healthy controls. METHOD Fourteen schizophrenic patients and fourteen matched controls performed a facial affect identification task during fMRI acquisition. The emotional task included an intuitive emotional condition (matching emotional faces) and a more cognitively demanding condition (labeling emotional faces). Individual analysis for each emotional condition, and second-level t-tests examining both within-, and between-group differences, were carried out using a random effects approach. Psychophysiological interactions (PPI) were tested for variations in functional connectivity between amygdala and other brain regions as a function of changes in experimental conditions (labeling versus matching). RESULTS During the labeling condition, both groups engaged similar networks. During the matching condition, schizophrenics failed to activate regions of the limbic system implicated in the automatic processing of emotions. PPI revealed an inverse functional connectivity between prefrontal regions and the left amygdala in healthy volunteers but there was no such change in patients. Furthermore, during the matching condition, and compared to controls, patients showed decreased activation of regions involved in holistic face processing (fusiform gyrus) and increased activation of regions associated with feature analysis (inferior parietal cortex, left middle temporal lobe, right precuneus). CONCLUSIONS Our findings suggest that schizophrenic patients invariably adopt a cognitive approach when identifying facial affect. The distributed neocortical network observed during the intuitive condition indicates that patients may resort to feature-based, rather than configuration-based, processing and may constitute a compensatory strategy for limbic dysfunction.

Dopaminergic contribution to the regulation of emotional perception

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role in motor and cognitive function. However, the impairment of emotional processes in neurologic and psychiatric pathologies involving the dopaminergic system (Parkinson disease, schizophrenia, autism, Attention Deficit Hyperactivity Disorder, Huntington disease, frontal lobe lesions), as well as the influence that administration of dopaminergic agonists/antagonists exert on the processing of emotion, suggest a role for DA in emotional processes. Moreover, emotional processes are dependent upon a variety of structures, the majority of which form part of the limbic system and are subject to DA innervation. In reviewing the literature, the amygdala emerges as a brain structure critical for emotional processing. It may also be implicated in deficits in emotional recognition found in two major disorders where DAs implication is clear: Parkinson disease and schizophrenia. In addition, the amygdalas response to emotional tasks is likely to be altered by the administration of both agonist and antagonist dopaminergic drugs. Experimental studies reinforce the idea of a dopaminergic contribution to emotional response, as suggested by biochemical, pharmacologic, and lesion experiments. Although the implication of the dopaminergic system in emotional processing appears to be clearly documented, the contribution of specific DA receptor subtypes, or of the DA cotransmitters cholecystokinin and neurotensin, or even glutamate, is, however, still unclear. Altogether, these observations suggest that DA has, undoubtedly, a direct and/or indirect role in the full emotional process.

Influence of visual cues on gait in Parkinson's disease: Contribution to attention or sensory dependence?

Sensory cueing is used for a long time to improve gait in patients with Parkinsons disease. This has been established for visual cues such as stripes on floor and for rhythmic auditory cues. Concerning visual cueing two main mechanisms of action have been suggested and may be suitable depending on the instruction given to the patients. Stripes placed on the walking surface may draw attention to the stepping process if patients are talked to put their feet on the stripes. In another paradigm, the stripes on floor are just used to enhance the optical flow and the motion of the stripes is essential to improve gait. These findings are not found in normal controls suggesting that patients with Parkinsons disease are more dependent on dynamic visual cues for gait control than controls. Several common characteristics exist between attention and sensory contribution in gait control. First, their potential beneficial effect may be contre-balanced by a negative influence: visual information may be helpful for gait in patients or may disrupt locomotion and induce freezing (for example passing a door). Attention focused on gait allows a partial correction of the troubles by intentional modulation of the stride length but a dual task flowing attention away produces deterioration. Another point is that both strategies are probably used by the central nervous system to compensate deficits: visual dependence to compensate an impaired kinesthetic feed-back and attentional processing to alleviate automaticity in locomotion and so, to by-pass the deficit of internal cueing.

Antipsychotic and anxiolytic properties of risperidone, haloperidol, and methotrimeprazine in schizophrenic patients.

The subjects were 62 patients hospitalized for acute exacerbations of schizophrenia and were randomly assigned to receive risperidone (mean dose, 7.4 mg/day), haloperidol (7.6 mg/day), or methotrimeprazine (100 mg/day) for 4 weeks. Clinical improvement, defined a priori as a 20% reduction in total Positive and Negative Syndrome Scale (PANSS) scores at end point, was attained by 81% of the risperidone patients, 60% of the haloperidol patients, and 52% of the methotrimeprazine patients (p < 0.05). The reductions in total PANSS and Clinical Global Impression Scale severity scores from baseline to end point were significantly greater in the risperidone patients than in the other two groups. Reductions in scores on the Psychotic Anxiety Scale were significantly greater in the risperidone patients than the methotrimeprazine patients; the difference between haloperidol and methotrimeprazine was not significant. Extrapyramidal symptoms (scores on the Extrapyramidal Symptom Rating Scale) were more severe in the haloperidol patients than in the other two groups, but few differences were apparent between risperidone and methotrimeprazine patients. It is concluded that risperidone is an effective antipsychotic and anxiolytic agent in schizophrenic patients.

Effect of ascorbic acid in patients with Charcot–Marie–Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A. METHODS This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot-Marie-Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779. FINDINGS The median change in CMTNS from baseline to 12 months was 0.5 points (95% CI -0.3 to 1.4) for the placebo group (n=62), 0.7 points (0.0 to 1.4) for the 1 g ascorbic acid group (n=56), and -0.4 points (-1.2 to 0.4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0.14). The occurrence of adverse events did not differ between the groups (p=0.74). INTERPRETATION Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown.