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We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients’ blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

Objective: To evaluate botulinum toxin treatment of hyperactive upper esophageal sphincter after first-time brainstem stroke. Design: A retrospective study. Subjects: Twelve patients with long standing dysphagia after brainstem vascular injury admitted to the rehabilitation department of a medical centre. Methods: All patients underwent clinical examination, videofluoroscopic study of swallowing and electromyography. Botulinum toxin was injected percutaneously under electromyographic guide. Outcomes were measured after two weeks and through a long follow up programme, which ranged from two to ten years. Results: A total of 75% of patients (9 of 12) had favourable outcomes. Two patients showed long lasting functional benefits after only one botulinum toxin injection, while seven patients required further treatments to maintain an adequate oral intake. In seven cases it was possible to remove percutaneous endoscopic gastrostomy. No relevant complications were observed. Conclusion: Botulinum toxin can improve severe dysphagia with elective hyperactivity of the upper esophageal sphincter in patients with or without unilateral paresis of the inferior constrictor muscle and in absence of a nuclear involvement of the IXth and Xth cranial nerves. The outcome could be unsatisfactory in the cases of oral phase involvement, bilateral lesion of the inferior constrictor muscle and when there is velopharyngeal insufficiency.

426 patients with peripheral motor or sensory neuropathies were recruited and randomly assigned to 2 treatment groups in a double-blind, 30-day, prospective trial comparing L-acetylcarnitine (LAC) [1000 mg/day intramuscularly for the first 10 days then 2000 mg/day orally for the remaining 20 days] with placebo. Treatment efficacy was assessed by commonly employed electrophysiological tests performed at baseline and at the end of treatment. Safety and tolerability evaluations were performed on the entire patient population, although the statistical analysis for efficacy was restricted to the 298 patients with lower-than-normal nerve conduction velocities (CVs) at baseline. Among patients with impaired motor nerve function, a statistically significant improvement in mean CV (p < 0.01 vs placebo) was detected in LAC-treated individuals with mononeuropathies, whereas no statistical difference emerged between the LAC- and placebo-treated groups in patients with motor nerve poly neuropathies. In contrast, there were statistically significant differences between the LAC and placebo groups in terms of improvement in mean CV in patients with sensory nerve mononeuropathies (p < 0.05) and in those with sensory nerve polyneuropathies (p < 0.05). Only 17 patients reported poor tolerability to treatment, and only 7 of the 32 patients who were withdrawn from the study did so because of adverse events. Our trial demonstrated the efficacy of LAC in improving electrophysiological nerve conduction properties in patients with sensory or motor neuropathies.

Background: selective activation and the contempo- rary recording of A delta and C fibers from Yap laser on the scalp is a new neurophysiological assessment, allowing the selective activation of the nociceptive system. Objectives: to evaluate if the damage of the nociceptive system was related to post herptic nevral-gia (PHN) development in a sample of 26 patients affected by Herpes zooster (HZ); secondly to assess if the impairment of thermal pathway and PHN development were related. Methods: Thirty-two patients were selected for the study, 26 of these were included in the study, whereas 6 were excluded because of cog- nitive impairment. All 26 study patients were sub- mitted to LEP analysis at baseline (T0) and after six months (T1), and the correlation between clinical thermal disease and the development of PHN was monitored. Results: pain duration was evidenced by the presence or absence of an instrumental signal in patients with acute HZ infection. There was total concordance between the absence of LEP signal and pain duration. The concordance between the clinical thermal disease and the pain duration was statisti- cally significant for 43% of the sample. Conclusions: our results suggested a possible role of LEP for PHN prognosis estimation; indeed, most patients affected by acute HZ, with absence of instrumental LEP signal had pain > 6 months. We also noted a significant (43% of cases) clinical concordance between the thermal pathway damage, the absence of instrumental signal and PHN development. Further studies are needed to address this issue.

Objective To compare the effect of electrical stimulation applied before and after botulinum toxin injection. Subjects Eight healthy subjects. Methods Both extensor digitorum brevis muscles were injected with low fixed doses of botulinum toxin. Subjects received a 20-min session of electrical stimulation before botulinum toxin injection for the right foot and after the injection for the left foot. Percentage changes in compound muscle action potential amplitude were calculated at different intervals over a 60-day period. Results A reduction in compound muscle action potential percentage was measured at every time-point, both for the muscles stimulated before injection of botulinum toxin and for those stimulated after injection. The compound muscle action potential percentage was always lower on the side stimulated after injection of botulinum toxin. A reduction in compound muscle action potential percentage was measured on the 7th and 15th days in all extensor digitorum brevis muscles examined. On the 15th day the compound muscle action potential percentage was 38.8 (right foot) vs 24.1 (left foot) (p=0.0117). A slow recovery was observed after this period. Conclusion Electrical nerve stimulation enhances the effect of botulinum toxin to a greater extent if applied after injection rather than before. The short stimulation time used in our study gave similar results to those seen in previous research using longer application times.

OBJECTIVE In multiple avulsions of the brachial plexus, the search for extraplexal donor nerves in the hope of achieving motor neurotization is a major goal. We explored the possibility of using the hypoglossal nerve as a transfer point to reanimate muscles in the upper limb. METHODS The hypoglossal nerve was used as a donor nerve for neurotization in seven patients with avulsive injuries of the brachial plexus. The surgical technique—an end-to-side microsuture using approximately half of the nerve fascicles—is basically the same as that used in the hypoglossal nerve-facial nerve jump graft, which is a well-known technique in facial nerve reanimation. The recipient nerves were the suprascapular (two patients), the musculocutaneous (one patient), the posterior division of the upper trunk (two patients), and the medial contribution to the median nerve (two patients). RESULTS In spite of a connection documented by electromyography and selective activation in three of seven patients, the functional results in our patients were extremely disappointing: no patient had an outcome better than M1 in the reinnervated muscles. CONCLUSION This technique was of no help to the patients and thus has been abandoned at our institution.

Objective: To assess the efficacy and tolerability of acetyl-L-carnitine (levacecarnine; LAC) versus placebo in the treatment of diabetic neuropathy, mainly by evaluating the effects of treatment on electrophysiological parameters and pain symptoms. Design: This was a multicentre (n = 20), randomised, double-blind, placebo-controlled, parallel-group study. Patients: 333 patients meeting clinical and/or neurophysiological criteria for diabetic neuropathy were enrolled. Interventions: Patients were randomised to treatment with LAC or placebo. LAC (or placebo) was started intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the study (355 days). Main outcome parameters and results: The main efficacy parameter was the effect of treatment on 6- and 12-month changes from baseline in nerve conduction velocity (NCV) and amplitude in the sensory (ulnar, sural and median) and motor (median, ulnar and peroneal) nerves. The effect of treatment on pain was also evaluated by means of a visual analogue scale (VAS). Among the 294 patients with impaired electrophysiological parameters at baseline, those treated with LAC showed a statistically significant improvement in mean NCV and amplitude compared with placebo (p < 0.01). The greatest changes in NCV (at 12 months) were observed in the sensory sural nerve (+5.7 m/sec in the LAC group vs +1.0 m/sec in the placebo group), sensory ulnar nerve (+2.9 vs +0.1 m/sec, respectively) and motor peroneal nerve (+2.7 vs −0.2 m/sec), whereas the greatest changes in amplitude were recorded in the motor peroneal nerve (+2.2 vs +0.1 mV). After 12 months of treatment, mean VAS scores for pain were significantly reduced from baseline by 39% in LAC-treated patients (p < 0.0 vs baseline) compared with 8% in placebo recipients. LAC was well tolerated over the study period. Conclusions: LAC was effective and well tolerated in improving neurophysiological parameters and in reducing pain over a 1-year period. LAC is, therefore, a promising treatment option in patients with diabetic neuropathy.

We report on the genetic and molecular characterisation of an Italian family with a late-onset, autosomal dominant transthyretin amyloidosis. The transthyretin gene was analysed by polymerase chain reaction (PCR), restriction generating PCR, and sequencing, allowing us to discover in one allele a novel point mutation. It consists of a G to C transversion at position 1692 of the genomic sequence, leading to a Thr for Arg substitution at the position 34 of the polypeptidic chain. This mutation is associated with a severe sensory-motor peripheral neuropathy and a restrictive cardiomyopathy.

Botulinum neurotoxins type A and E (BoNT/A and /E) are metalloproteases with a unique specificity for SNAP-25 (synaptosomal-associated protein of 25 kDa), an essential protein component of the neuroexocytotic machinery. It was proposed that this specificity is based on the recognition of a nine-residue sequence, termed SNARE motif, which is common to the other two SNARE proteins: VAMP (vesicle-associated membrane protein) and syntaxin, the only known substrates of the other six clostridial neurotoxins. Here we report on recent studies which provide evidence for the involvement of the SNARE motif present in SNAP-25 in its interaction with BoNT/A and /E by following the kinetics of proteolysis of SNAP-25 mutants deleted of SNARE motifs. We show that a single copy of the motif is sufficient for BoNT/A and /E to recognise SNAP-25. While the copy of the motif proximal to the cleavage site is clearly involved in recognition, in its absence, other more distant copies of the motif are able to support proteolysis. We also report on studies of poisoning human neuromuscular junctions with either BoNT/A or BoNT/E and describe the unexpected finding that the time of recovery of function after poisoning is much shorter in the case of type E with respect to type A intoxication. These data are discussed in terms of the different sites of action of the two toxins within SNAP-25.

A total of 1097 patients, mean age 53.8 +/- 15 years, with peripheral mono-, multi- or polyneuropathy of various aetiologies, were enrolled in a multicentre, open-label, noncomparative, prospective clinical trial to evaluate the short-term tolerability and efficacy of L-acetylcarnitine (LAC). The drug was administered intramuscularly at a dosage of 1000 mg/day for the first 10 days, then orally at a dosage of 2000 mg/day for a further 20 days. Standard laboratory tests were used to evaluate safety and tolerability. Treatment efficacy was assessed clinically in the whole population, and in a subgroup of patients with 'lower than normal' baseline nerve conduction velocities (CVs), neurophysiological investigations were also performed at the end of the treatment period. After 30 days' therapy, there were no changes in vital signs or in blood tests. Only 18 patients reported poor tolerability of the treatment, mainly because of gastrointestinal events, and only 6 withdrew from the study because of these adverse events. The general and local (i.e. injection site) tolerability of LAC was rated highly by both patients and investigators. Neurological examination revealed that a significant percentage of patients with altered indices at baseline had normal indices by the end of the treatment period. The percentage of normalised patients varied from 11.9% for muscular trophism to 29.1% for the topographic score according to the different parameters taken into account in the neurological examination. Disease was rated as improved by 83.1% of investigators and 84.2% of patients. In patients with reduced CVs, significant increments were also recorded for motor and sensory nerves. This study demonstrates that LAC is well tolerated when given either intramuscularly or orally. The beneficial effects of short-term therapy in subjects with peripheral mono-, multi- or polyneuropathy should be confirmed by long-term studies.

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.

Item does not contain fulltext Brody disease is an inherited myopathy associated with a defective function of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 1 (SERCA1) protein. Mutations in the ATP2A1 gene have been reported only in some patients. Therefore it has been proposed to distinguish patients with ATP2A1 mutations, Brody disease (BD), from patients without mutations, Brody syndrome (BS). We performed a detailed study of SERCA1 protein expression in muscle of patients with BD and BS, and evaluated the alternative splicing of SERCA1 in primary cultures of normal human muscle and in infant muscle. SERCA1 reactivity was observed in type 2 muscle fibers of patients with and without ATP2A1 mutations and staining intensity was similar in patients and controls. Immunoblot analysis showed a significant reduction of SERCA1 band in muscle of BD patients. In addition we demonstrated that the wild type and mutated protein exhibits similar solubility properties and that RIPA buffer improves the recovery of the wild type and mutated SERCA1 protein. We found that SERCA1b, the SERCA1 neonatal form, is the main protein isoform expressed in cultured human muscle fibers and infant muscle. Finally, we identified two novel heterozygous mutations within exon 3 of the ATP2A1 gene from a previously described patient with BD.

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.

The optimal conversion ratio between Dysport and Botox--the two botulinum neurotoxin type A products (BoNT-As) supported by the larger bulk of evidence-has been extensively debated, because of its broad medical and economic implications. The article discusses the available evidence on the conversion ratio between Dysport and Botox in adults affected by spasticity, cervical dystonia, blepharospasm and hemifacial spasm, with a focus on clinical trials that specifically addressed this issue. In addition, some suggestions on the conversion ratio between Dysport and Xeomin can be extrapolated, since Xeomin has the same efficacy and safety profile as Botox and is exchangeable with Botox with a 1:1 conversion ratio. Taken together, the findings retrieved from this literature research suggest that a conversion ratio of 3:1 (Dysport:Botox)--or even lower--can be considered appropriate for the treatment of the above-mentioned conditions. Higher conversion ratios may lead to an overdosing of Dysport, with a potential increased incidence of adverse events. Therefore, we recommend that physicians using both products consider using a lower conversion factor as a guide, adjusting it upwards as required based on the specific characteristics and response to treatment of each patient.

Background Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. Methods Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. Results The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. Conclusions This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.

We studied the electrophysiological changes occurring in six patients with tethered cord syndrome. Evidence of spinal malformations was provided by magnetic resonance imaging. The functional assessment of the spinal cord was performed by analysing both spinal and cortical somatosensory evoked potentials. The evoked electrospinogram was recorded from the thoracic and lumbosacral spinous processes. The N22 lumbosacral potential was selectively affected, being rostrocaudally displaced and reduced in amplitude or even absent in patients with neurological signs indicating a segmental lower cord lesion. Inter-peak somatosensory evoked potentials latency was normal in all cases, suggesting that ascending axonal potentials in the dorsal column fibres may be synchronized. Segmental potentials of the lumbosacral response, originating from the post-synaptic activity of dorsal horn interneurons, are selectively affected in this syndrome resulting from the rostrocaudal displacement of the spinal cord due to tethering. Our findings in the clinical field are consistent with previous experimental evidence indicating a different sensitivity of the gray vs. white matter to progressive stretching.

An international panel has recently proposed consensus definitions for pediatric multiple sclerosis and related disorders. These are important diagnostic improvements, but exceptions have been acknowledged. Further insight about clinical overlap between pediatric multiple sclerosis and all forms of relapsing acute disseminated encephalomyelitis may be gained from long-term follow-up. We report an 8-year follow-up of a girl who developed multiple episodes of central nervous system demyelination at the age of 3 years consistent with multiphasic acute disseminated encephalomyelitis. At 10 years of age (7 years after the first clinical event), she developed progressive cognitive deterioration, mood disorder, and headache, suggesting a secondary progressive form of multiple sclerosis. Magnetic resonance imaging and cerebrospinal fluid analysis were equivocal while visual evoked potentials were the sole test in favor of a diagnosis of multiple sclerosis. A multifaceted approach may be needed when dealing with atypical cases of demyelinating disease in young children.

Background and purpose Neurodegeneration in spinocerebellar ataxia type 1(SCA1) and 2(SCA2) is associated with white matter(WM) damage. Voxel-Based Morphometry(VBM), histogram analysis of mean diffusivity(MD) and Tract-Based Spatial Statistics(TBSS) enable an in vivo quantitative analysis of WM volume and structure. We assessed with these 3 techniques the whole brain WM damage in SCA1 and SCA2. Patients and methods Ten patients with SCA1, 10 patients with SCA2 and 10 controls underwent MRI with acquisition of T1-weighted and diffusion tensor images. The results were correlated with severity of clinical deficit. Results VBM showed atrophy of the brainstem and cerebellar WM without significant differences between SCA1 and SCA2. Focal atrophy of the cerebral subcortical WM was also present. Histogram analysis revealed increased MD in the brainstem and cerebellum in patients with SCA1 and SCA2 which in SCA2 was more pronounced and combined with mild increase of the MD in the cerebral hemispheres in SCA2. In SCA1 and SCA2 TBSS revealed decreased fractional anisotropy(FA) in the inferior, middle and superior cerebellar peduncles, pontine transverse fibres, medial and lateral lemnisci, spinothalamic tracts, corticospinal tracts and corpus callosum. The extent of tract changes was greater in SCA2 patients who also showed decreased FA in the short intracerebellar tracts. In both diseases VBM, histogram and TBSS results correlated with clinical severity. Conclusions Brain WM damage featuring a pontocerebeellar atrophy is similar in SCA1 and SCA2 but more pronounced in SCA2. In both diseases it correlates with severity of the clinical deficit.

This study investigated the possible prognostic factors for relapse, and the diagnostic criteria for multiple sclerosis and related disorders, in pediatric acute disseminated encephalomyelitis. The study population comprised 24 Italian children with a mean age at onset of 6.9 years, and a mean follow-up time of 52.8 months (range, 12-180). Clinical, neurophysiologic, spinal-fluid, neuroradiologic, and outcome features were investigated. All patients but 2, who were reclassified as exhibiting clinically isolated syndromes, fulfilled the new classification criteria for acute disseminated encephalomyelitis recently proposed by the International Pediatric Multiple Sclerosis Study Group. Three patients relapsed after 3 months, 2 years, and 8 years, respectively. By the second attack, the diagnosis of multiple sclerosis, as well as of multiphasic disseminated encephalomyelitis, could be rendered using the revised criteria of McDonald et al. Long-term follow-up seemed to confirm a chronic disease course in 2 children. We could not identify features at onset to predict outcomes of patients. However, early in follow-up, the appearance of oligoclonal immunoglobulin G bands in spinal fluid and the persistence of visual-evoked potential abnormalities were associated with poor outcomes.

Experimental methods involving painful electrical stimulation of a peripheral nerve showed the existence of a minimum stimulation frequency capable of inducing cramp, termed "threshold frequency" (TF). Our aim was to test an alternative method to induce fasciculations and cramps electrically. Two daily sessions of electrical stimulation of the abductor hallucis muscle were performed in 19 volunteers on 3 days: stimulation trains of 150 monophasic square pulses (duration 152 micros) of increasing frequency (current intensity 30% higher than maximal; frequency of the first trial, 4 pps; recovery between trials, 1 min) were delivered to the main muscle motor point until a cramp developed. Once a cramp was induced the protocol was repeated after 30 min. To verify by electromyography that cramp occurred, a surface electrode array was placed between the motor point and the distal tendon. Ambient and skin temperature were kept constant in all sessions. Fasciculations and cramps were elicited in all subjects. We observed the following median (interquartile range) values of TF: day 1 (session 1), 13 (6) pps; day 1 (session 2), 16 (4) pps; day 2 (session 1), 16 (6) pps; day 2 (session 2), 18 (6) pps; day 3 (session 1), 17 (4) pps; day 3 (session 2), 18 (8) pps. TF intersession intraclass correlation coefficients were 0.82, 0.92, and 0.90 for days 1, 2, and 3, respectively. TF interday intraclass correlation coefficient was 0.85. The absence of pain due to the stimulation and the demonstration of TF reliability support the use of our method for the study of involuntary muscle phenomena.

Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.

Since Alan Scott's research, botulinum toxin (BoNT) has been used in several diseases or conditions characterised by muscular overactivity. BoNT acts on either neuromuscular or autonomic cholinergic junctions. Seven different serotypes are known, with antigenic specificity and different therapeutic profiles. BoNT is made up of a heavy chain, involved in binding and membrane translocation, and a light chain, involved in blocking neuroexcytosis. Each serotype shares a specific acceptor on the presynaptic membrane of a cholinergic junction. The available BoNT preparations differ in toxicity, purity and stability. Injection of the neurotoxin produces several modifications at a neuromuscular junction. Axonal sprouting, muscular fibre atrophy, and new end-plates are the most evident histological events after BoNT treatment. They appear to be reversible in untreated muscles. Diffusion can occur at first by haematogeneous or local BoNT spread. Several factors, such as dose, volume, site of injection, muscle size, and muscular fascia, can influence the amount of diffusion and possible side-effects. After prolonged BoNT treatment patients can become unresponsive. Antibodies directed against BoNT have been observed with ELISA or mouse bioassay. Different serotypes have been used to treat non-responder patients. Novel toxins with lower immunogenicity and prolonged clinical efficacy are required for more effective treatment.

In recent decades, functional laryngeal surgery has become a widespread method of treating glottic and supraglottic neoplasms, since it ensures an oncological outcome comparable to that of radical surgery and functional results that are conducive to a good quality of life. The most common postoperative complaints for this type of surgery are swallowing disorders, which can thwart good surgical results, especially when severe. Five supracricoid laryngectomees with swallowing disorders unresolved by speech therapy were treated by percutaneous injection of botulinum toxin under electromyographic control. All patients presented marked improvement in their complaints. A single session of botulinum toxin type A treatment resolved the dysphagia in all cases.

Objectives : Botulinum neurotoxin serotype A (BoNT/A) is a valid therapy for dystonia but repeated BoNT/A injections may induce a clinical immuno-resistance that could be overcome by using other BoNT serotypes. In vitro experiments and our preliminary investigations in vivo, indicate that botulinum neurotoxin serotype C (BoNT/C) could be an effective alternative to BoNT/A. Moreover, in cultured neurons ‘in vitro' BoNT/C has been reported to be more toxic than BoNT/A. Methods : To verify this possibility, we compare the effect of BoNT/C and BoNT/A on the motor units count in humans by using the electrophysiological motor unit number estimation (MUNE) technique (‘multiple point nerve stimulation'). Preliminarily, BoNT/C and BoNT/A dosage was calibrated in a mouse hemidiaphragm neuromuscular junction preparation. Subsequently, 8 volunteers were treated with 3IU of BoNT/C in the extensor digitorum brevis muscle of one foot and 3IU of BoNT/A in the contralateral one. Other 4 subjects were similarly injected at higher doses (10IU of BoNT/C or BoNT/A) to detect a possible dose-toxic effect. Results : In both groups, no statistically significant variations in MUNE counting or single motor unit potential size were detected after 4 months from injections, when it was evident a recovery from the BoNTs blockade. Conclusions : We conclude that BoNT/C, similarly to BoNT/A, is safe and effective in humans and it could be proposed for a clinical use.

Palmoplantar hyperhidrosis is frequently observed in patients with a clinical history of chronic abnormal alcoholic intake. It can be related to peripheral or central mechanisms such as abnormal spontaneous activity in peripheral damaged fibres; receptor hypersensitivity; compensatory incremented activity in segmentary anhidrosis; or impairment of central sweat control. With the aim of quantifying this phenomenon and of identifying its possible origin, sympathetic skin response (SSR) analysis was performed in 20 chronic alcoholic patients with clinical diffuse acral hyperhidrosis, compared with 30 normal subjects and 2 patients affected by primary palmoplantar hyperhidrosis (PPH). SSRs were recorded by disc electrodes place on the hands and feet, simultaneously. At the hand level two recording sites were selected: palm-dorsum proximally and ventral-dorsal tip of the third finger distally. Attention was paid to the number of SSR after a single endogenous or exogenous stimulus. The alcoholic patients were divided into two groups, with and without mild polyneuropathy. Both patient groups showed synchronous SSR at recording sites, with the same pattern and the normal delay between upper and lower arms. In the control group one response was generally related to a single stimulus; if more responses were elicited an evident adaptation was shown; in the two groups of patients an increase of the waves was observed in all the recording sites without any adaptation. The SSR profile described in alcoholic patients was observed also in PPH. The pattern of SSR waves in alcoholic patients seems to suggest a possible central origin of this type of hyperhidrosis.

Botulinum toxin serotypes A and E (BoNT/A and /E) cleave the carboxy-terminus of synaptosomal associated protein-25 (SNAP-25) removing nine and 26 residues, respectively. To investigate the effect of these lesions of the same target molecule, 11 volunteers were injected with 3 IU of BoNT/A in the extensor digitorum brevis (EDB) muscle of one foot and with 3 IU of BoNT/E in the contralateral one. In addition, seven volunteers were similarly injected with mixtures of BoNT/A+BoNT/E. Compound muscular action potential (CMAP) was measured at different time intervals and the percentage variation of CMAP (%CMAP) was calculated. Unexpectedly, a much faster recovery of %CMAP after BoNT/E injections was observed. Double poisoned EBD muscles recovered similarly to BoNT/E. So, a larger deletion of the SNAP-25 molecule caused by BoNT/E leads to a faster functional recovery.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive hereditary neuromuscular disorder, transmitted in an autosomal dominant fashion. Its clinical expression is highly variable, ranging from almost asymptomatic subjects to wheelchair dependent patients. The molecular defect has been linked to chromosome 4q35 markers and has been related to deletions of tandemly repeated sequences located in the subtelomeric region detected by probe p13E-11 (D4F104S1). We describe a pair of monozygotic male twins affected by FSHD, carrying an identical de novo p13E-11 EcoRI fragment of paternal origin and showing great variability in the clinical expression of the disease, one being almost asymptomatic and the other severely affected. Their medical history was the same, with the exception of an anti-rabies vaccination performed at the age of 5 in the more severely affected twin. We hypothesise that the vaccination might have triggered an inflammatory immune reaction contributing to the more severe phenotype.

We assessed peripheral nerve function during and after lower-limb lengthening by callotasis in 14 patients with short stature, using motor conduction studies. Four patients with short stature of varying aetiology showed unilateral and one showed bilateral weakness of foot dorsiflexion. Both clinical and electrophysiological abnormalities consistent with involvement of the peroneal nerve were observed early after starting tibial callotasis. There was some progressive electro-physiological improvement despite continued bone distraction, but two patients with Turner’s syndrome had incomplete recovery. A greater percentage increase in tibial length did not correspond to a higher rate of peroneal nerve palsy. The function of the posterior leg muscles and the conduction velocity of the posterior tibial nerve were normal throughout the monitoring period. The F-wave response showed a longer latency at the end of the bone distraction than in basal conditions; this is probably related to the slowing of conduction throughout the entire length of the nerve.

Botulinum toxin is now widely used in the treatment of several hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign cramp-fasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection significantly lowered our patients' clinical cramp severity scores (mean +/- SD: before, 3.80 +/- 0.44; after, 1.40 +/- 0.54), left muscle strength unchanged and significantly increased their cramp threshold frequencies (before, 4.22 +/- 2.26 Hz; after, 10.0 +/- 3.74 Hz). The clinical benefit induced by botulinum toxin lasted about 3 months. Botulinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 +/- 0.19 fasciculations/sec; after, 0.45 +/- 0.11 fasciculations/sec). These findings show that local intramuscular injections of botulinum toxin provide effective, safe, and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.

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.

The aim of this work is to define the pattern of summation of the muscle fibre twitches in the surface mechanomyogram (MMG) generation process. For this purpose, two groups of muscle fibres of the extensor digitorum communis (EDC) were stimulated using needle electrodes. To these two artificial (because made by different muscle fibre types) motor units (MU1 and MU2), we administered: (a) separate stimulations: 3 and 9 Hz (MU1), 8 and 20 Hz (MU2) for 5 s; (b) simultaneous stimulation: 3 Hz (MU1) + 8 Hz (MU2); 9 Hz (MU1) + 20 Hz (MU2) for 5 s. The mechanomyograms, recorded during separate stimulation of MU1 and MU2, were linearly summated for the generation of a mechanomyographic signal to be compared with the one detected during (b) stimulation procedure. The bispectrum and the bicoherence of the generated MMG (MMGg) and of the MMG recorded during simultaneous (MMGs) stimulation were calculated for the detection of the quadratic non-linearity in the system responses. It was found that the MMGg and MMGs presented difference in the bispectrum and bicoherence index only when the 9–20 Hz stimulation pair was considered. In conclusion, our data indicate that the MMG derives from the summation of the active muscle fibres twitches and that the latter is linear only for very low firing rates. This is to be carefully considered when studies on MMG modelling will be undertaken.

Rat soleus muscles were partially or totally denervated by sectioning the radicular nerve L5 or the radicular nerves L3 through L6, respectively. Three days after these procedures, fibrillation potentials were not observed in the case of partial denervation, whereas they were clearly detectable after total denervation. At later times, spontaneous spike activity also developed in the partially denervated muscles. The difference in time of onset of fibrillation between partially and totally denervated muscles was confirmed by a more gradual increase in the number of acetylcholine receptors and a greater sensitivity to tetrodotoxin of the former muscles. These differences between partially and totally denervated muscles are interpreted on the basis of the different amounts of nerve breakdown products generated in the two situations.

Plasma total and free carnitine concentrations were measured in 14 patients during a 4-hour hemodialysis session at 40-min intervals. Although postdialysis carnitine levels were lower than predialysis levels, they did not drop progressively and rebound occurred early or late. While no relationship was seen between pre- and postdialysis carnitine values, an inverse correlation was found when the predialysis value was compared with an end-dialysis to predialysis ratio. Our data are not consistent with a first-order elimination kinetics of the molecule and suggest that during dialysis carnitine may be actively released from tissue stores to plasma pool. The finding of an inverse correlation between the fractional change (post-pre ratio) of plasma carnitine and its predialysis level suggests that plasma carnitine supply from cells is more active when plasma carnitine levels are lower.

Visual evoked potentials were studied in 30 insulin-dependent diabetic children and adolescents. Thirty percent of the subjects had evidence of significant abnormalities. No correlation was found between visual evoked potentials and age, duration of diabetes, metabolic control, and retinopathy.

Weanling and adult rats were intraperitoneally injected with d -carnitine for 40 days. After 15 days of treatment a statistically significant depletion in the muscle levels of free and total l -carnitine was observed, but after 40 days this depletion became slight and statistically not significant. These findings suggest the presence of a compensatory mechanism acting on the inhibition of l -carnitine transport into skeletal muscle fibres.