SUMMARYObjectives: Botulinum toxin A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation. Such mechanism may be involved in peripheral neuropathic pain.Methods: A possible direct analgesic effect of BTX-A pain processing was investigated in 29 patients with focal painful neuropathies and mechanical allodynia using a randomized double-blind placebo-controlled design. Patients received a one time intradermal administration of BTX-A (20 to 190 units) into the painful area.Outcome measures, evaluated at baseline, then at 4, 12 and 24 weeks, included average spontaneous pain intensity, quantified testing of thermal and mechanical perception and pain, allodynia to brushing (area, intensity), neuropathic symptoms, clinical global impression and quality of life.Results : BTX-A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from 2 weeks after the injection to 14 weeks. These effects correlated with the preservation of thermal sensation at baseline (p <0.05).BTX also improved allodynia to brush and decreased pain thresholds to cold, without affecting perception thresholds. There were sustained improvements in the proportion of responders (Number Needed to Treat for 50 % pain relief: 3.03 at 12 weeks), neuropathic symptoms and general activity. Most patients reported pain during the injections, but there were no further local or systemic side effects.Interpretation : These results indicate for the first time that BTX-A may induce direct analgesic effects in patients with chronic neuropathic pain independent on its effects on muscle tone and suggest novel indications for BTX-A in analgesia.Key words: neuropathic pain -botulinum toxin A -double blind randomized studyallodynia Word count : abstract words 254 ; manuscript words : 3369

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Background and Purpose: A patent foramen ovale has been reported to be significantly more frequent in young stroke patients than in matched control subjects, and paradoxical embolism has been suggested as the main mechanism of stroke in this situation. The present study was designed to test this hypothesis.

Post-operative analysis of the anatomical location of active contacts is difficult, and all the methods used are debatable. The relationship between the anatomical location of active contacts and the clinical effectiveness of stimulation is unclear. It would be necessary to take into account the volume of the electrode contacts and the diffusion of the stimulation. We can nevertheless assume that the interface between dorso-lateral STN, zona incerta and Forel's fields could be directly involved in the effects of stimulation.

Macrophagic myofasciitis (MMF), a condition newly recognized in France, is manifested by diffuse myalgias and characterized by highly specific myopathological alterations which have recently been shown to represent an unusually persistent local reaction to intramuscular injections of aluminium-containing vaccines. Among 92 MMF patients recognized so far, eight of them, which included the seven patients reported here, had a symptomatic demyelinating CNS disorder. CNS manifestations included hemisensory or sensorimotor symptoms (four out of seven), bilateral pyramidal signs (six out of seven), cerebellar signs (four out of seven), visual loss (two out of seven), cognitive and behavioural disorders (one out of seven) and bladder dysfunction (one out of seven). Brain T(2)-weighted MRI showed single (two out of seven) or multiple (four out of seven) supratentorial white matter hyperintense signals and corpus callosum atrophy (one out of seven). Evoked potentials were abnormal in four out of six patients and CSF in four out of seven. According to Poser's criteria for multiple sclerosis, the diagnosis was clinically definite (five out of seven) or clinically probable multiple sclerosis (two out of seven). Six out of seven patients had diffuse myalgias. Deltoid muscle biopsy showed stereotypical accumulations of PAS (periodic acid-Schiff)-positive macrophages, sparse CD8+ T cells and minimal myofibre damage. Aluminium-containing vaccines had been administered 3-78 months (median = 33 months) before muscle biopsy (hepatitis B virus: four out of seven, tetanus toxoid: one out of seven, both hepatitis B virus and tetanus toxoid: two out of seven). The association between MMF and multiple sclerosis-like disorders may give new insights into the controversial issues surrounding vaccinations and demyelinating CNS disorders. Deltoid muscle biopsy searching for myopathological alterations of MMF should be performed in multiple sclerosis patients with diffuse myalgias.

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

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