Rocco Quatrale

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 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.

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an ‘Official MDS translation,’ the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

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.

Motor evoked responses to paired cortical magnetic stimulation in Parkinson's disease

We evaluated cortical excitability in patients with Parkinsons disease (PD) using paired magnetic stimulation. This recent technique allows to study the cortical inhibition after motor evoked potential (MEP) and its modulation at different intensities of stimulation and interstimulus intervals (ISIs). At low stimulus intensity and at ISIs of 40-75 ms we observed, in PD patients, a greater test MEP inhibition, which might be due to a lower facilitatory effect of conditioning MEP on the motor cortex. At high stimulus intensity, in PD patients, a consistent inhibition of test MEP persisted and, at ISIs of 75-150 ms, it did not reach the amplitude of conditioning MEP as in normal subjects. Some clinical and neurophysiological features, like a silent period of shorter duration, demonstrated in PD patients a decrease of the inhibitory input to the motor cortex. On the contrary, the persistence of test-MEP inhibition at high stimulus intensity could also suggest a prevalence of inhibitory activity when an effective and phasic activation of the corticospinal system is required.

Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease

Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6‐hydroxydopamine‐hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinsons disease. In this study, we investigated whether elevation of N/OFQ expression in 6‐hydroxydopamine‐hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinsons disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (−20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ∼3.5‐fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinsons disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.

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.

Emerging issues on selection criteria of levodopa carbidopa infusion therapy: considerations on outcome of 28 consecutive patients.

Many studies confirmed the efficacy and safety of continuous infusion of intrajejunal levodopa/carbidopa gel (CIILG) for advanced Parkinson’s disease (PD). Although this treatment is widely used, definite inclusion/exclusion criteria do not exist. In this prospective open-label study, we evaluated the long-term outcome in 28 consecutive patients and sought to detect any predictive factor to identify the best candidates for CIILG therapy. The assessment was carried out routinely at baseline, after 6 months and every year with UPDRS III–IV, FOG Questionnaire, non-motor symptoms scale, PD questionnaire (PDQ-8), cognitive and psychiatric status evaluation (MMSE, FAB, NPI) and caregiver’s quality of life. 17/28 patients reached the 24-month follow-up. A statistically significant beneficial effect was shown on motor complications in short- and long-term follow-up, also on axial symptoms like gait disturbances. A concomitant improvement in PDQ8 score was observed, with a parallel mild amelioration, but not significant, on Caregivers QoL. When classified according to their outcome on QoL, the only predictive positive factor was less severe at Neuropsychiatric Inventory (NPI) score at baseline. Considering the improvement in motor scores (duration of “off” period), the more advanced age was associated with a poorer outcome. Our results confirmed a sustained efficacy and safety in long-term follow-up and suggest that younger age at operation and absence or mild presence of psychiatric/behavioural symptoms could be considered valid predicting factors in selecting the best candidates for this efficacious therapy.

Pattern of motor evoked response to repetitive transcranial magnetic stimulation

The changes in motor pathway excitability, induced by pairs or trains of transcranial magnetic stimuli, were studied. The motor evoked potential (MEP) pattern depended on the interstimulus interval (ISI), the stimulus intensity and the type of coil employed. At low intensity, using either an 8-shaped or a circular coil, there was a test MEP inhibition at ISIs of 50-150 msec. During trains of stimuli, this inhibition showed a periodic trend with an interval of 250-300 msec. At high stimulus intensity we observed a progressive disappearance of test MEP inhibition which was incomplete with an 8-shaped coil and complete, reaching an MEP facilitation, with a circular coil. The inhibition observed at low intensity might be due to cortical inhibitory mechanisms. The effect found at high intensity and with the circular coil could depend on the activation of deeper and at higher threshold cortico-spinal structures. This hypothesis, however, does not explain the simultaneous delay of the test MEP latency which might depend on the activation of different cortico-spinal pathways.