V. Tugnoli

Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in human

Botulinum neurotoxin (BoNT) serotype A is commonly used in the treatment of focal dystonia. Nevertheless, some patients are or become resistant to this serotype. Consequently, other different serotypes have to be used. A comparison of the neuromuscular blockade induced by BoNT type A and C in the extensor digitorum brevis muscles of voluntary subjects was studied, by evaluating the amplitude variation over the time (until 90 days) of the compound muscular action potential elicited by supramaximal electrical stimulation of the peroneal nerve at the ankle. A very similar effect and temporal profile, was observed for each serotype. On this basis, two patients with idiopathic facial hemispasm and one with blepharospasm were treated with BoNT serotype C with very beneficial long lasting effects.

Management of Parotid Sialocele With Botulinum Toxin

INTRODUCTION Parotid sialoceles are relatively common as a complication of trauma with penetrating injury to the parotid gland or as a complication after parotidectomy. The management of parotid sialoceles has been unsatisfactory and numerous methods of treatment have been described. A case is presented of a patient who developed a sialocele after a penetrating injury to the parotid area. Initially conservative measures (percutaneous aspiration and pressure dressing) were unsuccessfully applied to manage the sialocele. More aggressive approaches were avoided by injecting botulinum toxin into the parotid gland. The present paper describes this simple and effective sialocele management technique.

Different types of botulinum toxin in humans.

In humans, botulinum neurotoxin (BoNT) serotype A (BoNT/A) is a useful therapeutic tool, but different BoNT serotypes may be useful when a specific immune resistance related to BoNT/A is proved. BoNT serotype F (BoNT/F) was injected into human muscles but its effects are shorter compared to BoNT/A, whereas BoNT serotype B (BoNT/B) is effective in humans only if injected at very high doses. BoNT serotype C (BoNT/C) has a general profile of action similar to BoNT/A. Nevertheless, a comparison between these different BoNTs in human has not yet been reported. To establish the general profile of these different BoNTs in humans and the spread in near and untreated muscles we conducted an electrophysiological evaluation in 12 healthy volunteers by injecting BoNT/A (BOTOX 15MU), BoNT/B (NeuroBloc 1500MU), BoNT/F (15MU), BoNT/C (15MU) and a saline solution (placebo) in the abductor digiti minimi muscle (ADM) in a double‐blind manner. The compound muscle action potential (CMAP) amplitude variation, before and at 2, 4, 6 and 8 weeks after the injections, was evaluated in the ADM, the fourth dorsal interosseus, the first dorsal interosseus and the abductor pollicis brevis APB. We detected an earlier recovery for BoNT/F when compared to the other BoNTs. No significant differences in the local or distant BoNT spread was observed among the different serotypes. We conclude that in humans, BoNT/B and BoNT/C have a general profile similar to BoNT/A and as such these serotypes could be alternative therapies to BoNT/A. BoNT/F might be useful when only a short duration of neuromuscular blockade is required.

Botulinum neurotoxins: mechanism of action and therapeutic applications

Recent studies have led to the discovery of the molecular lesions in motor neurons caused by botulinum neurotoxins. These neurotoxins are metalloproteinases that enter the cytosol and very specifically cleave protein components of the neuroexocytosis apparatus. Consequently, acetylcholine cannot be released and the muscle is paralysed. For this reason, botulinum neurotoxins are increasingly being used to treat a variety of conditions where a functional paralysis of neuromuscular junctions is useful as therapy.

Botulinum toxin treatment in the facial muscles of humans: Evidence of an action in untreated near muscles by peripheral local diffusion

In a population of subjects with blepharospasm and facial hemispasm treated for the first time with botulinum toxin type A (BT) in the orbicularis oculi muscle, we performed an electrophysiologic study (compound muscle action potential and motor evoked potential) to assess whether BT effect could be detected in near untreated muscles (orbicularis oris and masseter).There was a significant BT action in nearly untreated muscles with different peripheral innervation that can be explained by local diffusion of the drug. NEUROLOGY 1996;46: 1158-1160

Botulinum Toxin type A reduces capsaicin-evoked pain and neurogenic vasodilatation in human skin

Abstract The effect of Botulinum Toxin type A (BoNT/A) on pain and neurogenic vasodilatation induced by application to the human skin of thermal stimuli and capsaicin was evaluated in a double blind study. A capsaicin cream (0.5 ml of a 0.075%) was applied to the skin of both forearms of eighteen subjects randomly pretreated with either BoNT/A (Botox®) or 0.9% saline (NS). Capsaicin was applied to a skin area either inside (protocol A) or adjacent to the BoNT/A treated area (protocol B). Pre‐treatment with BoNT/A did not affect thermal‐specific and thermal‐pain thresholds (by quantitative sensory testing). However, capsaicin‐induced pain sensation (by a visual analogue scale), flare area (by acetate sheet) and changes in cutaneous blood flow (CBF, by laser Doppler flowmetry) were reduced when capsaicin was administered inside (protocol A) the BoNT/A treated area. In Protocol B, capsaicin‐induced pain was unchanged, and capsaicin‐induced flare/increase in CBF were reduced only in the area treated with BoNT/A, but not in the BoNT/A untreated area. Results indicate that (i) BoNT/A reduces capsaicin‐induced pain and neurogenic vasodilatation without affecting the transmission of thermal and thermal‐pain modalities; (ii) reduction in capsaicin‐induced pain occurs only if capsaicin is administered into the BoNT/A pretreated area; (iii) reduction in neurogenic vasodilatation by BoNT/A does not contribute to its analgesic action. BoNT/A could be tested for the treatment of conditions characterised by neurogenic inflammation and inflammatory pain.

The role of gustatory flushing in Frey's syndrome and its treatment with botulinum toxin type A

Abstract. After parotid surgery, gustatory sweating and flushing occur more frequently, the former reportedly in 15–100 % of cases, while no reliable data are available for the latter. Although botulinum toxin (BoNT) is effective in controlling sweating, little is known about its effect on flushing. In 17 patients suffering from Freys syndrome after parotid surgery, we studied the gustatory flushing phenomenon as compared to gustatory sweating, analyzing their frequency, area, type of stimulus and response to BoNT administration. Cutaneous blood flow (CBF) was monitored by laser Doppler flowmetry (LDF) on affected and unaffected areas of the cheek in basal conditions and after meals, before and then 1 month after starting the BoNT injections. The Minor test was used to identify the sweating area. Flushing was observed in 7 of 17 patients after masticatory activity, spicy meals or citrus fruits. No clinical data correlated with any presence of flushing. Flushing regressed completely after BoNT administration and CBF reached similar values in the affected and unaffected sites. No adverse effects were observed. BoNT administration proved an effective and safe treatment for gustatory sweating and flushing in patients with Freys syndrome.

Botulinum Toxin for Pain

Botulinum toxin (BTX) injection is being increasingly used ‘off label’ in the management of chronic pain. Data support the hypothesis of a direct analgesic effect of BTX, different to that exerted on muscle. Although the pain-reducing effect of BTX is mainly due to its ability to block acetylcholine release at the synapse, other effects on the nervous system are also thought to be involved. BTX affects cholinergic transmission in both the somatic and the autonomic nervous systems. Proposed mechanisms of action of BTX for pain relief of trigger points, muscular spasms, fibromyalgia and myofascial pain include direct action on muscle and indirect effects via action at the neuromuscular junction. In vitro and in vivo data have shown that BTX has specific antinociceptive activity relating to its effects on inflammation, axonal transport, ganglion inhibition, and spinal and suprasegmental level inhibition. Our review of the mechanisms of action, efficacy, administration techniques and therapeutic dosage of BTX for the management of chronic pain in a variety of conditions shows that although muscular tone and movement disorders remain the most important therapeutic applications for BTX, research suggests that BTX can also provide benefits related to effects on cholinergic control of the vascular system, autonomic function, and cholinergic control of nociceptive and antinociceptive systems. Furthermore, it appears that BTX may influence the peripheral and central nervous systems. The therapeutic potential of BTX depends mainly on the ability to deliver the toxin to the target structures, cholinergic or otherwise. Evidence suggests that BTX can be administered at standard dosages in pain disorders, where the objective is alteration of muscle tone. For conditions requiring an analgesic effect, the optimal therapeutic dosage of BTX remains to be defined.

Clinical use of non-a botulinum toxins: Botulinum toxin type C and botulinum toxin type F

Botulinum neurotoxin (BoNT) serotype A is commonly used in the treatment of focal dystonia, but some patients are primarily or become secondarily resistant to it. Consequently, other serotypes have to be used when immuno-resistance is proven. In the literature, patients with focal dystonia have been treated with BoNT serotype F with clinical benefit but with short lasting effects. Recently, BoNT serotype C has been used with positive clinical outcome. An update on the clinical use of BoNT serotype F and BoNT serotype C is provided.

Pallidal stimulation for segmental dystonia: Long term follow up of 11 consecutive patients†

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6‐12‐24‐36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective.