A Delphi consensus statement of the Neuropathic Pain Special Interest Group of the Italian Neurological Society on pharmacoresistant neuropathic pain.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

Intraoperative monitoring of sensory part of the trigeminal nerve using blink reflex during microvascular decompression for trigeminal neuralgia.

Intraoperative monitoring during cerebellopontine angle surgery is widely accepted. While techniques which monitor cranial motor nerves are commonly used, monitoring the sensory afferents has been challenging. Considering the reflex arc, blink reflex (BR) might be useful in monitoring the sensory part of the trigeminal nerve, the brainstem connections and the facial nerve. We describe the case of a patient who developed hemifacial hypoesthesia after microvascular decompression surgery for trigeminal neuralgia. Intraoperative BR showed a severe loss of R1 amplitude. BR might be a useful intraoperative technique to monitor the sensory part of the trigeminal nerve.

Peripheral neuropathy in 30 duodopa patients with vitamins B supplementation.

OBJECTIVES: Peripheral neuropathy (PN) is a significant concern and potential cause of withdrawal in patients with Parkinson's disease (PD) treated with Levodopa/Carbidopa Intestinal Gel (LCIG) infusion. Vitamin B deficiency and/or hyperhomocysteinemia levodopa-related are considered possible causative factors. In this study, we evaluated PN incidence in LCIG-PD patients treated since the beginning of infusion with vitamins B supplementation. MATERIALS & METHODS: In this prospective open-label pilot study, 30 consecutive patients with PD on LCIG infusion were evaluated with clinical, neurophysiological, and biochemical assessments for a mean follow-up of 42.4 months (range 24-72). All evaluations were repeated every 6 months. RESULTS: At baseline, 21 of 30 presented no signs or symptoms of PN, and 9 of 30 had pre-existing chronic PN. In whole population, a progressive worsening in nerve conduction studies of sural sensory and peroneal motor nerves was observed during the long-term follow-up. 4 of 21 patients, with normal clinical, electrophysiological assessment at baseline, developed distal symmetrical axonal polyneuropathy that remained asymptomatic during the long-term follow-up. Patients with pre-existing PN (9 of 30) showed a mild worsening of electrophysiological features during the period of observation. In none PN was cause of discontinuation of LCIG therapy. No incident cases of acute-subacute PN were documented. No correlation was found with age, sex, Levodopa dosage, duration of levodopa exposure, and homocysteine plasma levels. CONCLUSION: In this consecutive series of 30 patients with PD on LCIG infusion, with early and continuous vitamins B integration, we observed a low rate (19%) of new onset peripheral polyneuropathy that remained stable after long-term follow-up. Larger studies, controlled, with blinded evaluation, are needed to confirm these findings.

Space-time distribution of the ALS incident cases by onset type in the Health District of Ferrara, Italy.

OBJECTIVES: An ecological study in the resident population of the Health District (HD) of Ferrara, Italy, has been carried out to establish the distribution in space and time of the amyotrophic lateral sclerosis (ALS) incident cases according to the disease onset type and gender in the period 1964-2009. MATERIAL AND METHODS: The hypothesis of a uniform distribution was assumed. RESULTS: The incident cases of spinal onset ALS and bulbar onset ALS were evenly distributed in space and time in both men and women. The spinal onset ALS incident cases distribution according to gender was significantly different from the expected in the extra-urban population (20 observed cases in men 95% Poisson confidence interval 12.22-30.89, expected cases in men 12.19; six observed cases in women 95% Poisson confidence interval 2.20-13.06, expected cases in women 13.81), whereas no difference was found in the urban population. The spinal onset ALS incidence was higher in men than in women in the extra-urban population (difference between the rates = 1.53, 95% CI associated with the difference 0.52-2.54), whereas no difference between sexes was found in the urban population. CONCLUSIONS: The uneven distribution according to gender of the spinal onset ALS incident cases only in the extra-urban population suggests the involvement of a gender related environmental risk factor associated with the extra-urban environment. Despite some limits of the spatial analysis in the study of rare diseases, the results appear consistent with the literature data.

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests.

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.

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.

Spinal anesthesia and minimal invasive laminotomy for paddle electrode placement in spinal cord stimulation: technical report and clinical results at long-term followup.

OBJECT: We arranged a mini-invasive surgical approach for implantation of paddle electrodes for SCS under spinal anesthesia obtaining the best paddle electrode placement and minimizing patients' discomfort. We describe our technique supported by neurophysiological intraoperative monitoring and clinical results. METHODS: 16 patients, affected by neuropathic pain underwent the implantation of paddle electrodes for spinal cord stimulation in lateral decubitus under spinal anesthesia. The paddle was introduced after flavectomy and each patient confirmed the correct distribution of paresthesias induced by intraoperative test stimulation. VAS and patients' satisfaction rate were recorded during the followup and compared to preoperative values. RESULTS: No patients reported discomfort during the procedure. In all cases, paresthesias coverage of the total painful region was achieved, allowing the best final electrode positioning. At the last followup (mean 36.7 months), 87.5% of the implanted patients had a good rate of satisfaction with a mean VAS score improvement of 70.5%. CONCLUSIONS: Spinal cord stimulation under spinal anesthesia allows an optimal positioning of the paddle electrodes without any discomfort for patients or neurosurgeons. The best intraoperative positioning allows a better postoperative control of pain, avoiding the risk of blind placements of the paddle or further surgery for their replacement.

Awake surgery in low-grade gliomas harboring eloquent areas: 3-year mean follow-up.

Low-grade gliomas are slow-growing tumors invading eloquent areas and white matter pathways. For many decades these tumors were considered inoperable because of their high tropism for eloquent areas. However, the young age of the patients and the inescapable anaplastic transformation have recently suggested more aggressive treatments. We analyzed the neurological and neuro-oncological outcome of 12 patients who underwent surgery fully awake for the resection of LGG, harboring eloquent areas. 10 right- and 2 left-handed patients underwent pre-operative assessment: Karnofsky Performance Status, Edinburgh Handedness Inventory Score; neuropsychological and neurophysiological evaluations, according to the tumor location. During surgery we performed: sensory-motor-evoked potentials, continuous electro-corticography and bipolar/monopolar cortico-subcortical mapping during neuropsychological tests. The resection rate was calculated with neuro-imaging elaboration software. No permanent post-operative deficits were reported; 2 patients improved after surgery. No impairment of cognitive functions was reported. The KPS improved in 8 patients and was steady in the others. The mean resection rate was 78.3%. The resection allowed the control of pre-operative seizures without increasing the drug intake. Awake surgery allowed a good resection rate despite the eloquent location of the tumors, without post-operative deficit. The neuropsychological outcome was unchanged after surgery. The resection seems to improve seizure control. All the patients came back to normal life and work. In conclusion, awake surgery is reliable and feasible in removal of LGG, even if invading the main eloquent areas and networks. All the patients experienced a normal life after surgery, without permanent deficits.

Pharmacological differences and clinical implications of various botulinum toxin preparations: a critical appraisal.

Three different type A botulinum neurotoxins (BoNTAs) - onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA) - are currently marketed in Europe to treat several conditions. Differences between BoNTA preparations, which depend on their specific biotypes and manufacturing processes, lead to clinically relevant pharmacotherapeutic dissimilarities. All three available products are separately recognized and reviewed in American Academy of Neurology guidelines. The neurotoxin load/100U is likewise different among the different BoNTAs, with the result that the specific potency of the 150kD BoNTA neurotoxin is calculated as 137 units/ng for onabotulinumtoxinA, 154 units/ng for abobotulinumtoxinA, and 227 units/ng for incobotulinumtoxinA. It is important for clinicians to have all three BoNTAs available in order to choose the most suitable preparation for the specific indication in the single patient. Commercially available BoNTAs must be recognized as different from one another, and therefore as non-interchangeable. The essential experience of the clinician is of the utmost importance in choosing the most appropriate treatment.

Metabolic findings on 3T 1H-MR spectroscopy in peritumoral brain edema.

BACKGROUND AND PURPOSE: Little is known about the metabolic properties of brain edema associated with tumors. This work was conducted on the basis of the assumption that, in the presence of intra-axial and extra-axial brain tumors, the white matter involved by the edema is a site of metabolic change that involves the structure of the myelin sheath. MATERIALS AND METHODS: Thirteen patients comprised our cohort affected by intra-axial and extra-axial cerebral tumors with a peritumoral T2-weighted MR signal hyperintensity as a result of edema, where MR spectroscopy showed no increase in choline-containing compounds. Measurements on proton MR spectroscopy (1H-MR spectroscopy) were performed with a 3T whole-body scanner with use of a point-resolved spectroscopy sequence for localization (TR, 2000 ms; TE, 35 ms), and the metabolites were quantified with the SAGE method. Peak intensities of the main metabolites were expressed as ratios of one another and were compared with values obtained in the white matter of the left frontal region in a control group of 16 healthy volunteers. RESULTS: Choline-to-creatine (Cho/Cr) and myo-inositol-to-creatine (mIns/Cr) signal intensity ratios were normal in all patients. N-acetylaspartate-to-creatine (NAA/Cr) and N-acetylaspartate-to-choline (NAA/Cho) ratios decreased in 4 patients. Glutamate plus glutamine-to-creatine (Glx/Cr) was increased in 10 patients. A resonance peak at 3.44 ppm, strongly suggesting the presence of glucose, was detected in all but 1 patient. Lactate was detected in 12 patients and lipids in 5. Moreover, the resonances that pertained to the aliphatic amino acids valine, leucine, and isoleucine were present in 12 patients. CONCLUSIONS: Our findings on MR spectroscopy confirmed the hypothesis that in the edema surrounding brain tumors, an energy-linked metabolic alteration was associated with injury to the myelin sheath.

Ex vivo HR-MAS Magnetic Resonance Spectroscopy of human gastric adenocarcinomas: a comparison with healthy gastric mucosa.

The present study reports the characteristics of the biochemical profile of human gastric adenocarcinoma in comparison with that of healthy gastric mucosa, using ex vivo HR-MAS Magnetic Resonance Spectroscopy. Healthy human mucosa is mainly characterized by the presence of small metabolites (more than 50 identified) and macromolecules, whereas the adenocarcinoma spectra are dominated by the presence of signals due to triglycerides, whose content on the contrary is very low in healthy gastric mucosa. The use of spin-echo experiments enable us to detect some metabolites in the unhealthy tissues and to determine their variation with respect to the healthy ones. We have observed that the Cho:ChoCC ratio changes from 20:80 in the healthy tissues to 80:20 in the neoplastic gastric mucosa.

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.

A comparison between in vivo and ex vivo HR-MAS 1H MR spectra of a pediatric posterior fossa lesion.

The present case report was aimed at identifying the molecular profile characteristic of a primitive neuro-ectodermal tumor (PNET) in a 3-year-old child affected by a lesion localized in the cerebellar region. The histological diagnosis was medulloblastoma. In vivo single voxel 1H magnetic resonance spectroscopy (MRS) shows high specificity in detecting the main metabolic alterations in the primitive cerebellar lesion; a very high amount of the choline-containing compounds and very low level of creatine derivatives and N-acetylaspartate. Ex vivo high resolution magic angle spinning (HR-MAS) 1H magnetic resonance spectroscopy, performed at 9.4 Tesla on the neoplastic specimen collected during surgery, allows for the unambiguous identification of several metabolites giving a more in-depth evaluation of the metabolic pattern of the lesion. The ex vivo HR-MAS MR spectra show that the spectral detail is much higher than that obtained in vivo and that, for example, myo-inositol, taurine and phosphorylethanolamine contribute to the in vivo signal at 3.2 ppm, usually attributed to choline-containing compounds. In addition, the spectroscopic data appear to correlate with some morphological features of the medulloblastoma. Consequently, the present study shows that ex vivo HR-MAS 1H MRS is able to strongly improve the clinical possibility of in vivo MRS and can be used in conjunction with in vivo spectroscopy for clinical purposes.

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.

In vitro and in vivo MRS study of human glioma metabolites.

In this study an in vitro multinuclear magnetic resonance spectroscopy (MRS) characterization of water soluble metabolites and of the lipid fraction obtained from 19 human gliomas (12 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 2 oligodendrogliomas) with a total of 27 surgical specimens, is reported. Moreover, some in vivo H-1 MRS results are shown. The regional metabolic heterogeneity of glioblastomas, according to their morphological heterogeneity, is documented. For glioblastomas a specific in vitro H-1 MRS metabolite profile cannot be defined. Low and high grade oligodendrogliomas showed characteristic choline/creatine and alanine/creatine metabolite ratios. The spectroscopical characterization of histopathological factors concerning malignant gliomas is shown.

In vivo single voxel 1H MRS of glial brain tumors: correlation with tissue histology and in vitro MRS.

Eighteen patients affected by glial brain tumors were examined by localized single voxel magnetic resonance spectroscopy (1H MRS). For all patients histological diagnosis was obtained after stereotactic biopsy or surgical removal of the tumor. Histological nuclear atypia, tumor cellularity, necrosis, vascular proliferation and percentage of Ki-67 positive cells in the total cell populations were evaluated. It was found that some of the in vivo 1H MRS parameters were related to the histological features of the tumor. In particular, the Choi/Cri metabolite ratio obtained from the neoplastic tissues paralleled the Ki-67 cell proliferation index. For some of the patients 1H and 13C in vitro high resolution magnetic spectroscopy of surgical specimens was also carried out. 1H MRS of aqueous extracts from different biopsy specimens of the same tumor furnished fine biochemical information on intratumor heterogeneity. The degree of histological vascular proliferation of the tumor was correlated to the presence of cholesteryl esters in the 13C spectrum of the lipid fraction of surgical specimens.

On the action of botulinum neurotoxins A and E at cholinergic terminals.

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.

Recovery cycle of the masseter inhibitory reflex after magnetic stimulation in normal subjects.

OBJECTIVE: To evaluate the differences in the recovery cycle of the masseter inhibitory reflex (MIR) obtained with electrical and magnetic stimulation. METHODS: In 31 healthy subjects we studied the MIR evoked by electrical or magnetic stimulation of the mental territory and the recovery cycle of this reflex with the paired stimuli technique at different interstimulus intervals (ISI), between 100 and 600 ms. RESULTS: Latency and area of the early and late silent periods (SPs) of the MIR were similar after electrical and magnetic stimulation. The recovery cycle of the test late SP was similar with the two kinds of stimulation, except for short ISIs. The main difference between the two kinds of stimulation was in the painful quality of the stimulus: the magnetic stimuli were always below pain threshold. CONCLUSIONS: As with electrical stimulation, it is possible to obtain a MIR with magnetic peripheral stimulation. The magnetic paired stimuli are equally effective in the evaluation of the recovery cycle of the MIR. The results demonstrate that magnetic stimulation is a useful tool in the evaluation of excitability of the trigeminal motoneuronal system, with little discomfort for the patient. They also confirm the unlikelihood of nociceptive afferences involvement.

Neurophysiological study of corticomotor pathways in restless legs syndrome.

OBJECTIVE: To test the variations in cerebral motor excitability in patients with primary restless legs syndrome (RLS) by using electrophysiological techniques. In RLS patients periodic legs movements (PLMs) in sleep and wake have been described and it is hypothesised that PLMs result from a sleep-related disinhibition of descending central motor inhibitory pathways. Moreover, in primary RLS, these modifications are still debated. METHODS: In 15 patients with primary RLS, transcranial magnetic stimulation (TMS) was carried out using several paradigms, particularly paired pulse TMS with short interstimulus intervals (ISI) in abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. RESULTS: Short ISI paired TMS showed a significant decrease in inhibition and increase in facilitation in ADM muscles. This result was even more evident in TA muscles of patients as compared to the controls and these modifications were more evident in the limbs which were more affected by PLM. Moreover, intracortical (corticocortical) inhibition (ICI) and intracortical facilitation (ICF) unchanged their biphasic time course. CONCLUSIONS: In our study the changes in short paired-pulse ICI and ICF revealed the presence of an altered excitability of central motor pathways, with good correlation with asymmetric distribution of symptoms.

Is Ross syndrome a dysautonomic disorder only? An electrophysiologic and histologic study.

OBJECTIVE: To define the involvement of peripheral nerve fibers in Ross syndrome. METHODS: Mechanical pain perception, tactile and thermal thresholds on hand, foot dorsum, thigh, median nerve orthodromic sensory conduction velocity (SCV) and motor conduction velocity (MCV), sural nerve antidromic SCV, peroneal nerve MCV, H-reflex, F-wave, median, tibial nerve somatosensory evoked potentials (SSEPs), perioral, hand CO(2) laser late (LEPs) and ultralate evoked potentials, sympathetic skin response (SSRs), cardiovascular, Minor sweat, silastic imprint, histamine, photopletysmographic and pupil pilocarpine tests, cutaneous innervation immunohistochemical techniques were studied in 3 patients with Ross syndrome. RESULTS: Quantitative sensory testing showed altered results in patients 1 and 2, and patient 3 had a slight impairment of mechanical pain perception. Nerve conduction, except for a median nerve distal reduction of sensory conduction in patient 1, F-wave and SSEP findings were normal; H-reflex was absent at rest in all patients. Hand LEPs were absent in patient 2, ultralate potentials were absent in patients 1 and 2. Skin biopsy showed a disease duration related reduction of unmyelinated and myelinated sensory fibers and a lack of unmyelinated autonomic fibers in all patients. CONCLUSIONS: Our data suggest that Ross syndrome is a degenerative disorder involving progressive sudomotor fibers, and then epidermal sensory unmyelinated and myelinated fibers.